Drug Interactions Flashcards
What enzyme metabolizes the majority of meds (75%)?
CYP 450 enzymes
Which specific CYP metabolizes 80% of the meds metabolized by CYP?
CYP 450 3A4 alone, or 3A4 and other enzymes
How do ALL enzymes in the body work?
By an enzyme-substrate system
What’s an enzyme?
Protein that performs some action
What’s a substrate?
A chemical that’s acted upon by an enzyme
What’s the main effect of an enzyme action?
Gen. inactivates drug metabolites (although, there are some times, the result in a toxic metabolite or beneficial metabolite)
Whats the first pass metabolism?
When the drug (substrate) passes through the gut wall and liver prior to reaching the systemic circulation
What are inducers?
Inducers are compounds (many of which are drugs) that either increase the PRODUCTION of the enzyme (by increasing the expression of the gene sequence that codes for the enzyme) or, increase the ACTIVITY of the enzyme
What’s the net effect of an inducer?
Increase the degree of drug metabolism, which results in LOWER blood levels of the substrate
Which med is one of the strongest inducers?
Rifampin
List the many enzymes that Rifampin induces
1A2
2C8, 2C9, 2C19
3A4
P-glycoprotein (P-gp) pump
Effect on warfarin dose, if pt is also started on Rifampin?
Warfarin dose will need to be increased 100-300% to maintain therapeutic INR
Effects of inducers on pro-drugs?
Inducer can increase the enzyme responsible for converting the substrate into a MORE active form (instead of less active or inactive form$
What’s the technical ref wrt prodrug conversion?
Bioactivation
What are inhibitors?
Compounds (many of which are drugs) that INHIBITS the activity of ENZYMES
Effect of inhibitor?
Enzyme inhibition results in LESS drug METABOLISM. T4 drug serum level (and therapeutic effect) will increase
Can result in drug toxicity
Effect of inhibitor on prodrug?
Inhibitor of the enzyme involved in bioactivation would block the production of the active form of the drug
Effects on Inducers on Substrate? On prodrugs?
Inducers DECREASE the conc of Substrate, EXCEPT with Prodrugs
T4 Inducers increase the conc of active metabolite of prodrug
Effects on Inhibitors on Substrate? On prodrugs?
Inhibitors INCREASE the conc of the substrate, EXCEPT prodrugs
T4 inhibitors decrease active metabolites of prodrugs
About 25% of drugs go through CYP 2D6, including many?
Pain and Psychiatric drugs
What are the practical considerations when d/c an inhibitor or inducer?
Consider the doses of other meds that have been increased or decreased bcuz of the use of the inducer or inhibitor.
So, before u d/c an inducer or inhibitor, check the status of the other meds they are using concurrently
Which has a “lag” time? Effect of the inhibition or Inducer?
Inducer: full effect may not be present for up to 2 wks. Similarly, it takes 2-4 wks for the induction to disappear completely
What’s P-glycoproteins (P-gp)?
Efflux transporters found in the gut and other organs.
They pump drugs back into the gut (to exit out of the body)
What happens if a drug is subject to efflux, and the transporter is inhibited by a different drug?
The substrate drug conc will INCREASE in the plasma
What happens to blood levels of a drug, if an inducer is given that causes the production of more pumps?
The blood levels of the substrate will DECREASE
What’s P-gp inducer?
Causes the creation of more of the P-gp and blood levels go down
Effect of P-gp on toxin?
If the toxin is a p-gp substrate, then it will reduce the amt of some toxin ingestion as well, by pumping them back into the gut
What’s P-gp inhibitor?
Inhibits the drug-pump-inhibitor and consequently, blood levels of the drug increase
List strong inhibitors of P-gp Efflux pump (results in increased in blood levels of the drug)
Itraconazole, Ketoconazole
Verapamil
Ritonavir; Lopinavir/Ritonavir; Indinavir/Ritonavir
Conivaptan
Clarithromycin; Eryhromycin
Amiodarone
Quinidine
List strong inducers of P-gp Efflux pump (results in decreased in blood levels of the drug)
Rifampin
Avasimibe
Carbamazepine
Phenytoin
St. John’s wort
Tipranivir/Ritonavir
List p-gp efflux pump substrates
Aliskiren
Colchicine
Dabigatran
Cyclosporine
Digoxin
Fexofenadine
Posaconazole
Ranolazine
Rivaroxaban
Saxagliptin
Tacrolimus
Look at pg 192 for CYP 450 substrates, inducers and inhibitors
LOOK!
List big inducers of CYP 450
PS PORCS (Big Inducers) - increase drug metabolism t4 lowering drug serum level
Phenytoin
Smoking
Phenobarbital Oxcarbazepine Rifampin (and Rifabutin, Rifapentine) Carbamazepine (and is an auto-inducer) St. John's wort
List big inhibitors of CYP 450
G PACMAN (Big Inhibitors) - reduce drug metabolism, t4 increasing serum drug level
Grapefruit
PIs - Protease Inhibitirs (esp Ritonavir)
Azoles antifungals - Fluconazole, Itraconazole, Ketoconazole,
Posaconazole, and Voriconazole
C - Cyclosporine and Cimetidine
Macrolides - Clarithromycin and Erythromycin, NOT Azithromycin, but
DO include the related compd, Telithromycin
Amiodarone (and Dronedarone)
Non-DHP CCBs (Diltazem and Verapamil)
Are all Macrolides big CYP inhibitors?
No!
Azithromycin is NOT a big inhibitor of CYP
Why’s cimetidine most difficult H2RA to use?
Big CYP inhibitor
Has androgen-blocking effects that can cause gynecomastia (swollen, or painful breast tissue or impotence)
What meds must be reduced by 30-50% when starting Amiodarone?
Digoxin
Warfarin
Quinidine
Procainamide
Simvastatin, Lovastatin and Atorvastatin
What drugs are most likely to be dosed with Amiodarone? Why?
Digoxin and Warfarin
Bcuz they are used in HF and arrhythmias
T/F? If warfarin or digoxin is on board first, the pharmacist must recognize the interaction and decrease the dose when amiodarone is started?
True
What’s medical conditions may cause an increase in digoxin levels?
Decline renal fxn
Hypokalemia
What other considerations (other than amiodarone mentioned previously) may be considered when digoxin is used?
Additive drugs that lower HR (< 60 BPM)
Primarily beta-blockers and non-DHP CCBs (Diltazem and verapamil)
Others include:
Dexmedetomidine (Precedex), Clonidine and Opioids
List drug interactions with grapefruit/ juice that are considered clinically significant
Rivaroxaban
- there could be an increased bleeding risk
Ticagrelor
QT prolongers + grapefruit/ juice = risk of torsades
Lurasidone
Quinidine
Effect of Lamotrigine + Valproate used concurrently
Increased risk of rash
List drugs not to use MAOI with
Ephedrine and analogs (Pseudoephedrine etc)
SSRIs, SNRIs, TCAs
Bupropion Buspirone Linezolid Lithium Meperidine Tramadol Levodopa Mirtazapine Dextromethropan Cyclobenzapine (and other skeletal muscle relaxants) Some of the triptans St. Johns wort Procarbazine Lorcaserin
Hydrocodone and Tramadol interaction?
Those on 2D6 inhibitors:
Fluoxetine
Paroxetine
Others
May be at increased risk of respiratory depression
DI with codeine?
Codeine undergoes conversion to morphine by 2D6 enzyme
DI with Oxycodone and Methadone?
Metabolized by 3A4
PDE-5 inhibitors
3A4 substrate
T4 avoid use with 3A4 inhibitor (inh metabolism leading to higher drug levels)
Which meds have chelation risks?
Quinolones, Tetracyclines
Which statins have the most risk of drug interaction?
LAS
Lovastation, Atorvastatin, Simvastatin
Which drugs increase statin drug levels?
Gemfibrozil
Macrolides
Which Calcineurin inhibitors are subject to significant rxn?
Tacrolimus and Cyclosporine
List drugs that bleeding risk is a concern in
Anticoagulants (warfarin, Dabigatran, Rivaroxaban, heparin and others)
AND
Antiplatelets (aspirin, dipyridamole, Clopidogrel, prasugrel, ticagrelor)
What dx condition may cause hyperkalemia risk?
Since potassium is renally cleared, severe renal dx causes hyperkalemia
List drugs that should be avoided if potassium is high at baseline (> 5 mEq/L)
Spironolactone
Eplerenone
ACEI ARBs Aliskiren Amiloride Triamterene Salt substitutes (KCL) Drospirenone-containing OCPs
List substances that may result in CNS depression
Alcohol Most pain meds (ALL opioids, some NSAIDs, other pain meds) Skeletal muscle relaxants Anticonvulsants Benzodiazepines Barbiturates Hypnotics Mirtazapine Trazodone Dronabinol Nabilone Propranolol Clonidine
List agents that may cuz QT prolongation and Torsades De Pointes
Mostly arrhythmia drugs and effect is additive
List agents that may cuz Ototoxicity
Salicylates Vanco Aminoglycosides Cisplatin Loop diuretics
Which meds can also increase INR?
Amiodarone
Trimethoprim/Sulfamethoxazole (Bactrim)
Ketoconazole
What do u need to separate Cipro from?
Multivitamin
Iron
Yogurt, cheese
What meds can increase risk of arrhythmias?
Fluconazole
Erythromycin
Ziprasidone
Primary location of CYP enzymes?
Liver and Intestines
