T2 Lecture 6: Drug Interactions

Question 1

What are the common risk factors associated with drug interactions?

Answer 1

Polypharmacy
Multiple prescribers
Multiple pharmacies
Genetic makeup
Special populations
Drug makeup

Question 2

What is the definition of a drug interaction?

Answer 2

Modification of the effect of one drug by the prior concomitant administration of another drug.

Question 3

What are the drug - dietary supplement interactions?

Answer 3

Rx, OTC, illicit substances
St. John’s Wort
Cocaine & antiHTNs

Question 4

What are the drug - food or drink interactions?

Answer 4

May cause interaction or prevent appropriate absorption
Doxycycline & milk
Metronidazole and alcohol

Question 5

What are the drug - disease interactions?

Answer 5

May be helpful in one disease but harmful in another
Beta blockers & asthma
NSAIDs & heart failure

Question 6

What are the categories of Drug Interaction Severity?

Answer 6

Category A: Unknown, no known interaction
Category B: Minor, No action needed. Minimal effect.
Category C: Moderate, monitor, may require adjustments.
Category D: Major, consider alternative, may be life-threatening.
Category X: Contraindicated, avoid combination, no concurrent use allowed.

Question 7

What are the pharmacodynamic drug interactions?

Answer 7

Additive effects on same receptor or additive effects on different receptors.

Synergistic effects: effect of 2 drugs magnified beyond what would be expected (aminoglycosides + penicillin)

Antagonist blocking agonist effects (Naloxone for opioids)

Question 8

What are some of the additive interactions pharmacodynamically?

Answer 8

Increased bleeding risk

Anticholinergic toxicity

Nephrotoxicity

QT Prolongation

Serotonergic Agents

Hyperkalemia (increased potassium)

Question 9

What drugs can cause increased bleed risk additively?

Answer 9

Anticoagulants like warfarin and DOACs (direct oral anticoagulants like rivaroxaban or apixaban or dabigatran)
Antiplatelets like clopidogrel/ticagrelor/prasugrel/aspirin
NSAIDs, SSRIs (Prozac, Lexapro, Zoloft), and SNRIs (Duloxetine, Venlafaxine)
Natural Products AKA the 5 Gs: garlic, gingko, ginger, ginseng, glucosamine.

Note:
Rivaroxaban = Xarelto
Apixaban = Eliquis
Dabigatran = Pradaxa
Clopidogrel = Plavix
Ticagrelor = Brilinta
Prasugrel = Effient
Duloxetine = Cymbalta
Venlafaxine = Effexor

Question 10

What drugs can cause anticholinergic toxicity additively?

Answer 10

Antihistamines (diphenhydramine)
SSRIs (Prozac, lexapro, zoloft), antipsychotics (risperidone, olanzapine, aripiprazole), TCAs (amitriptyline)
Muscle relaxants (baclofen)
Overactive bladder antimuscarinics (Oxybutynin)

Note: Relax allergies, mood, muscles, bladder
Diphenhydramine = Benadryl
Prozac = Fluoxetine
Lexapro = Escitalopram
Zoloft = Sertraline
Risperidone = Risperdal
Olanzapine = Zyprexa
Aripiprazole = Abilify
Amitriptyline = Elavil

Question 11

Anticholinergic side effects

Answer 11

dry mouth, constipation, urinary retention, bowel obstruction, blurred vision, inc heart rate, dec sweating

Question 12

What drugs can cause nephrotoxicity additively?

Answer 12

Aminoglycosides, vancomyin, amphotericin B
NSAIDs
IV Loop diuretics (furosemide, bumetanide, torsemide)
Chemotherapy (cisplatin, methotrexate), cyclosporine, tacrolimus

Note:
All of these drugs require renal clearance or act on the kidney.
Furosemide = Lasix.
Bumetanide = Bumex
Torsemide = Demadex

Question 13

What drugs can cause QT prolongation additively?

Answer 13

Antiarrhythmics - amiodarone, sotalol, dofetilide, ibutilide, procainamide, dronedarone

Antimicrobials - azoles, fluoroquinolones, macrolides

Antipsychotics - haloperidol, quetiapine, ziprasidone

Antidepressants - SSRIs, SNRIs, TCAs

Methadone, sumatriptan, ondansetron

Note:
Haloperidol = Haldol
Quetiapine = Seroquel
SSRI = selective serotonin reuptake inhibitor
SNRI = serotonin norepinephrine reuptake inhibitor
TCA = tricyclic antidepressant
Ondansetron = Zofran

Question 14

What drugs can boost serotonin additively?

Answer 14

All mood-altering meds, such as SSRIs, SNRIs, mirtazapine, trazadone, buspirone, TCAs, MAOis, lithium

Linezolid

Tramadol, methadone, meperidine

Dextromethorphan (cough medication)

Antiemetics (ondansetron)

Triptans (sumatriptan)

Note:
SSRI = selective serotonin reuptake inhibitor
SNRI = serotonin norepinephrine reuptake inhibitor
Mirtazapine = Remeron
TCA = tricyclic antidepressant (think amitriptyline)
MAOi = Monoamine oxidase inhibitor
Meperidine = Demerol (narcotic opioid)
Ondansetron = Zofran

Question 15

What drugs can cause hyperkalemia additively?

Answer 15

ACE inhibitors, ARBs, Sacubitril/Valsartan

K-sparing diuretics

Aldosterone antagonists

Sulfamethoxazole/trimethoprim

Tacrolimus/cyclosporine

Note:
ARB = angiotensin receptor blocker
Sacubitril/valsartan = Entresto (heart failure med)

Question 16

What are the four ways to affect absorption via drug interactions?

Answer 16

Chelation/complex formation
Change in pH
Increased motility time
p-gp efflux pumps

Question 17

What are the two ways to affect distribution via drug interactions?

Answer 17

Binding to alpha-1 acid glycoproteins
Binding to albumin

Question 18

What are the two ways to affect metabolism via drug interactions?

Answer 18

Phase I: oxidation, reduction, hydrolysis for inactivation// CYP P450 enzymes
Phase II: glucuronidation, sulfation, methylation for elimination

Question 19

What are the two ways to affect elimination via drug interactions?

Answer 19

Competition for transport
Change in urinary pH

Question 20

What are the CYP Inducers?

Answer 20

SCRAP GPS’S

Sulfonylureas (T2DM drugs)
Carbamazepine (antiseizure)
Rifampin/rifabutin (Abx for TB)
Alcohol use (chronic)
Phenobarbital (antiseizure)
Griseofulvin (antifungal)
Phenytoin (antiseizure)
Smoking
St. John’s Wort

Question 21

What do CYP inducers do?

Question 22

What are the CYP inhibitors?

Answer 22

PACMAN’S GM

Protease inhibitors (Anti HIV)
Amiodarone (antiarrhythmic)
Cyclosporine (immunosuppressant), chlorophenol (pesticide), cimetidine (GERD)
Macrolides (except azithromycin, Abx)
Azoles (antifungals)
Non-DHP CCBs (antiarrhythmics)
Sodium Valproate (antiseizure)
Grapefruit Juice
Metronidazole (Abx)

Question 23

What do CYP inhibitors do?

Answer 23

reduce enzymatic activity and metabolism
inc active drug availability
quick effect

Question 24

What drugs are 3A4 substrates?

Answer 24

Analgesics, anticoagulants (ACs), Antiplatelets, Antidiabetics, CV drugs, Immunosuppressants, Statins, HIV drugs, PDE-5 Inhibitors, Others

Question 25

What drugs are 2D6 substrates?

Answer 25

Analgesics, Antidepressants/antipsychotics, and others

Question 26

How much of the top 200 drugs are NOT metabolized by CYP enzymes?

Answer 26

33%, mostly via phase II metabolism.

Note:
Non-CYP metabolism usually has less drug interactions.
Most common are via UDP, NAT, and MAO.

Question 27

What toxicity can occur via Non-CYP enzyme metabolism?

Answer 27

Isoniazid toxicity

Question 28

What are some p-gp substrates?

Answer 28

Anticoagulants (apixaban, rivaroxaban, and dabigatran)
Antineoplastics (Docetaxel, vincristine)
Immunosuppressants (cyclosporine, tacrolimus)
Macrolides (clarithromycin)
HIV drugs (dolutegravir)
Digoxin

Question 29

What are some p-gp Inhibitors?

Answer 29

Antibiotics (clarithromycin, itraconazole, posaconazole)
HIV drugs (cobicistat, ritonavir)
Cardio drugs (verapamil, amiodarone, dronedarone, diltiazem)
Cyclosporine
Ticagrelor (Brilinta)

ABCCH

Question 30

Why do we use prodrugs?

Answer 30

We can use the CYP enzyme to convert it to the active metabolite, saving us money.
Reduces drug abuse, increases bioavailability
Risk lack of activity or potential toxicity

Question 31

What are the common prodrugs?

Answer 31

Codeine => morphine
Clopidogrel => active form
Lisdexamphetamine=> dexamphetamine
Fosphenytoin => phenytoin
Enalapril => enalaprilat
Valacyclovir => acyclovir
Cortisone => cortisol
Prednisone => Prednisolone
Primidone => Phenobarbital
Tramadol => active
Levodopa => dopamine
Diazepam = Oxazepam

Question 32

What are the common narrow therapeutic index drugs?

Answer 32

Aminoglycosides (G- ABx)
Vancomycin (ABx)
Digoxin (antiarrhythmic)
Warfarin (AC)
Tacrolimus (immunosuppressant)
Mycophenolate (immunosuppressant)
Cyclosporine (immunosuppressant)
Phenytoin (antiseizure)
Valproic acid/Sodium valproate (antiseizure)
Carbamazepine (antiseizure)
Theophylline (Bronchodilator)
Lithium (antimania)
Levothyroxine (HYPOthyrodism)

Question 33

What are the four ways we can affect warfarin via drug interactions?

Answer 33

Increased bleed risk via other ACs, NSAIDs, or SSRIs
Metabolism Interference via ABCDEF/Rifampin
Reduced Vit K production by gut flora via ABx
Interrupting the Vit K cycle via acetaminophen (1.5-2g chronically)

Question 34

What is the ABCDEF R of warfarin and its effects?

Answer 34

Increased INR (how thick blood is) = increased bleeding
Amiodarine
Bactrim
Cipro + other fluoroquinolones
Diflucan + other azoles
Erythromycin + other macrolides
Flagyl (Metronidazole)

Decreased INR = decreased bleeding
Rifampin (an inducer)

Question 35

If I want to start a patient on amiodarone but they are on warfarin already, how should I adjust my dosages?

Answer 35

I would expect a REDUCTION in my warfarin dosage by up to 50%, because amiodarone INCREASES INR.
(AKA bleeding more bc takes longer to clot)

Question 36

What are some common drug interactions with antiseizure meds? Describe what happens.

Answer 36

Lamotrigine + other antiseizures
Lamotrigine = substrate

Carbamazepine = Inducer
Valproic acid = Inhibitor

Lamotrigine + carbamazepine = drug gets metabolized faster, so I need MORE lamotrigine.

Lamotrigine + Valproic acid = drug barely gets metabolized, so I need LESS lamotrigine.

Question 37

What is the effect of a PDE-5 inhibitor and nitrate together?

Answer 37

They have additive effects of major vasodilation and consequently severe hypotension.

PDE-5 inhibitors = sildenafil/viagra or tadalafil
Nitrates = Nitroglycerins, isosorbides
Category X interactions.