Chapter 3: Learning Drug Interactions Flashcards
What is pharmacodynamics
The effect or change that a drug has on some type of organism, such as a human body
What is a pharmacodynamic drug interaction
When 2 or more drugs are given together and their end effects impact each other
Concomitant use of which 2 drug classes has a BBW that they may result in profound sedation, respiratory depression, coma and death
BZDs and opioids
____ is present when the effect from 2 drugs taken in combination is greater than the effect from simply adding the 2 individual effects together
Synergism
What is pharmacokinetics?
The effect the body has on the drug
What does ADME stand for
Absorption
Distribution
Metabolism
Excretion
What is chelation
when a drug binds to polyvalent cations (e.g., Mg, Ca, Fe) in another compound (e.g., antacids or iron supplements). The chelated complex cannot dissolve in the gut fluid and will pass out in the stool
Drugs with polyvalent cations or other binding properties should be separated from:
quinolones, tetracyclines, levothyroxine, and oral bisphosphonates
The majority of PK drug interactions occur during ____ in the _____
metabolism in the liver
____ is the primary route of drug excretion
Renal excretion
CYP450 enzymes are primarily expressed in the ____
liver
Which CYP enzyme metabolizes ~34% of all CYP-metabolized drugs
3A4
Prodrugs are taken by the patient in the ____ form and are converted by CYP450 enzymes into the ____ form
inactive
active
Codeine and tramadol should not be used in ultra-rapid metabolizers of ___
Why?
2D6
These prodrugs will be converted more rapidly to active drug, and with increased active drug concentration, this can cause toxicity/risk of possible fatality
Do not use clopidogrel with ____ inhibitors, including ___ and ____
2C19 inhibitors, including omeprazole and esomeprazole
With a prodrug, the active drug concentration decreases with a(n) _____
inhibitor (opposite effect since there are less functional enzymes to convert the prodrug to the active form)
What are the major CYP inhibitors
Remember G <3 PACMAN
- Grapefruit
- <3
- Protease inhibitors (PI), especially ritonavir
- Azole antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, and isavuconazole)
- Cyclosporine, cimetidine, cobicistat
- Macrolides (clarithromycin and erythromycin, but not azithromycin)
- Amiodarone (and dronedarone)
- Non-DHP CCBs (diltiazem and verapamil)
What are the major CYP inducers
Remember PS PORCS
- Phenytoin
- Smoking
- Phenobarbital
- Oxcarbazepine (and eslicarbazepine)
- Rifampin (and rifabutin, rifapentine)
- Carbamazepine (also an auto-inducer)
- St. John’s Wort
T/F: enzyme inhibition is fast & effects are seen within a few days and will end quickly when the inhibitor is d/c
True
When the inducer is stopped, it could take ____ for the induction effects to disappear completely
2-4 weeks
P-gp pumps in the cell membranes of the GI tract transport drugs and their metabolites out of the body by pumping them into the ___, where they can be excreted in the ____
gut
stool
When a drug inhibits Pgp, a drug that is a P-gp substrate will have (increased/decreased) absorption and the substrate drug level will (increase/decrease)
increased
increase
Common Pgp substrates per class:
- anticoagulants
- CV drugs
- immunosuppressants
- HCV drugs
- Others
- anticoagulants: apixaban, rivaroxaban
- CV drugs: digoxin, diltizaem, verapamil
- immunosuppressants: cyclosporine, tacrolimus
- HCV drugs: ombitasvir, paritaprevir, dasabuvir
- Others: colchicine
The recycling of an already-metabolized drug is called ______, which (increases/decreases) the duration of action of many drugs
enterohepatic recycling
increases
Amiodarone (inhibits/induces) multiple enzymes, including ____, which metabolizes the major warfarin isomer.
What action should be taken by the pharmacist?
Inhibits
CYP2C9
If using amiodarone first and adding warfarin: start warfarin at a lower dose of = 5 mg
If using warfarin first and adding amiodarone: decrease warfarin dose 30-50%, depending on the INR
Amiodarone inhibits P-gp and digoxin is a P-gp substrate. They also both increase the risk of ____.
What action should be taken by the pharmacist if using digoxin first and adding amiodarone?
Bradycardia; monitor for other drugs that decrease HR like BB, clonidine, diltiazem and verapamil
If using digoxin first and adding amiodarone, decrease the oral digoxin dose 50%
What is the interaction between digoxin and loop diuretics
Loops decrease K, Mg, Ca and Na. Digoxin toxicity risk is increased with decreased K and Mg levels and increased Ca levels
What action should be taken by the pharmacist when a patient is taking a statin and strong CYP3A4 inhibitor
Simvastatin and lovastatin are CI. Recommend a statin not metabolized by CYP450 enzymes (pitavastatin, pravastatin, rosuvastatin)
CYP2C9 inhibitors (increase/decrease) levels of warfarin, which (increase/decrease) INR and bleeding risk
increase levels of warfarin
increase INR
CYP2C9 inducers (increase/decrease) levels of warfarin, which (increase/decrease) INR and bleeding risk
Decrease levels of warfarin
decrease INR
Which drugs specifically include instructions not to take with grapefruit juice
Amiodarone, simvastatin, lovastatin, nifedipine, tacrolimus
What is the interaction between lamotrigine and valproate
Valproate decreases lamotrigine metabolism. Increased lamotrigine levels increase risk of serious skin reactions
What is the interaction between MAOi and drugs that increase Epi, NE, and DA and 5-HT
What action should be taken by the pharmacist
Blocking MAO with an MAOi will increase Epi, NE, DA and 5HT. High Epi, NE, and DA can cause hypertensive crisis. High 5HT can cause serotonin syndrome.
Use a 2-week washout period between serotonergic drugs and another antidepressant; if changing fluoxetine to an MAOi, wait 5 weeks
What is the interaction between MAOi and tyramine-rich foods/drinks
MAO metabolizes tyramine; if blocked, tyramine causes increased NE, with risk of hypertensive crisis
Which drugs are 2D6 inhibitors
Amiodarone, fluoxetine, paroxetine, fluvoxamine
Do not use an opioid prodrug that is metabolized by 2D6 (codeine, tramadol) in which patient population
Breast-feeding mother
What would happen to someone who is a smoker who takes antipsychotics, antidepressants, hypnotics, anxiolytics, caffeine, theophylline, or warfarin and quits?
What about current smokers?
Smokers who quit - when the inducer (cigarettes) is stopped, drug concentrations increase and can cause toxicity
Current smokers - the substrate drugs will have decreased levels
Which drugs, when used together, can cause serotonergic toxicity
Antidepressants MAOi Busprione Dextromethorphan Dihydroergotamine Lithium Lorcaserin Opioids Metoclopramide Triptans Natural products (St. John's Wort, I-tryptophan) Tegaserod
Which drugs, when used together, can increase bleeding risk
Anticoagulants Antiplatelets NSAIDs SSRIs/SNRIs Natural products (5Gs: garlic, ginger, ginkgo biloba, ginseng, glucosamine, plus vitamin E, willow bark, and fish oils)
Which drugs, when used together, can cause hyperkalemia risk
Spironolactone, eplerenone - highest risk RAAS drugs (ACEi, ARBs, aliskiren, sacubitril/valsartan) Amiloride, triamterene, KCl, tacolimus, cyclosporine, canagliflozin, SMX/TMP, and drosperinone-containing OCs
Citalopram and escitalopram are two SSRIs that can increase QT prolongation. What doses of the two should you not exceed in elderly patients > 60 years and in patients < 60?
Citalopram 40 mg/day
Citalopram 20 mg/day in patients > 60 years
Escitalopram 20 mg/day
Escitalopram 10 mg/day in patients > 60 years
Which combination of drugs has the highest risk of fatality when used in combination
Opioids + BZDs or other CNS depressants
Which drugs can cause ototoxicity?
Aminoglycosides, cisplatin, loop diuretics (especially rapid IV administration), salicylates, vancomycin
Which drugs can cause nephrotoxicity?
Aminoglycosides, amphotericin B, polymyxins, vancomycin Cisplatin CNIs: cyclosporine, tacrolimus Loop diuretics (especially IV) NSAIDs Radiographic-contrast dye
Which drugs can cause anticholinergic toxicity?
Paroxetine, TCAs, FGAs
Sedating antihistamines: diphenhydramine, brompheniramine, chlorpheniramine, doxylamine, hydroxyzine, cyproheptadine
Atropine, belladonna, dicyclomine, meclizine
Benztropine, trihexyphenidyl
Muscle relaxants, including baclofen, carisoprodol, cyclobenzaprine
Overactive bladder antimuscarinics, such as oxybutynin, darifenacin, tolterodine
CYP3A4 substrates
Analgesics: fentanyl, hydrocodone, methadone, oxycodone
Anticoagulants: apixaban, rivaroxaban, R-warfarin
CV drugs: amlodipine
Immunosuppressants: cyclosporine, tacrolimus, sirolimus
Statins: atorvastatin, lovastatin, simvastatin
PDE5i: avanafil, sildenafil, tadalafil, vardenafil
Others: ethinyl estradiol
CYP3A4 inducers
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, smoking, St. John’s Wort
CYP3A4 inhibitors
Anti-infectives: clarithromycin, erythromycin, azole antifungals
CV drugs: amiodarone, diltiazem, verapamil
Key HIV drugs: cobicistat, ritonavir and other protease inhibitors
Others: cyclosporine, grapefruit juice
1A2 substrates
R-warfarin
1A2 inducers
Carbamazepine, phenobarbital, phenytoin, rifampin, smoking, St. John’s Wort
1A2 inhibitors
Cipro, fluvoxamine
2C9 substrates
S-warfarin
2C9 inducers
Carbamazepine, phenobarbital, phenytoin, rifampin, smoking, St. John’s Wort
2C9 inhibitors
Amiodarone, fluconazole, metronidazole, SMX/TMP
2C19 substrate
Clopidogrel
2C19 inhibitors
Esomeprazole, omeprazole
2D6 substrates
Codeine, meperidine, tramadol, tamoxifen
