Drug Interactions

Question 1

What enzyme metabolizes the majority of meds (75%)?

Answer 1

CYP 450 enzymes

Question 2

Which specific CYP metabolizes 80% of the meds metabolized by CYP?

Answer 2

CYP 450 3A4 alone, or 3A4 and other enzymes

Question 3

How do ALL enzymes in the body work?

Answer 3

By an enzyme-substrate system

Question 4

What’s an enzyme?

Answer 4

Protein that performs some action

Question 5

What’s a substrate?

Answer 5

A chemical that’s acted upon by an enzyme

Question 6

What’s the main effect of an enzyme action?

Answer 6

Gen. inactivates drug metabolites (although, there are some times, the result in a toxic metabolite or beneficial metabolite)

Question 7

Whats the first pass metabolism?

Answer 7

When the drug (substrate) passes through the gut wall and liver prior to reaching the systemic circulation

Question 8

What are inducers?

Answer 8

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

Question 9

What’s the net effect of an inducer?

Answer 9

Increase the degree of drug metabolism, which results in LOWER blood levels of the substrate

Question 10

Which med is one of the strongest inducers?

Answer 10

Rifampin

Question 11

List the many enzymes that Rifampin induces

Answer 11

1A2

2C8, 2C9, 2C19

3A4

P-glycoprotein (P-gp) pump

Question 12

Effect on warfarin dose, if pt is also started on Rifampin?

Answer 12

Warfarin dose will need to be increased 100-300% to maintain therapeutic INR

Question 13

Effects of inducers on pro-drugs?

Answer 13

Inducer can increase the enzyme responsible for converting the substrate into a MORE active form (instead of less active or inactive form$

Question 14

What’s the technical ref wrt prodrug conversion?

Answer 14

Bioactivation

Question 15

What are inhibitors?

Answer 15

Compounds (many of which are drugs) that INHIBITS the activity of ENZYMES

Question 16

Effect of inhibitor?

Answer 16

Enzyme inhibition results in LESS drug METABOLISM. T4 drug serum level (and therapeutic effect) will increase

Can result in drug toxicity

Question 17

Effect of inhibitor on prodrug?

Answer 17

Inhibitor of the enzyme involved in bioactivation would block the production of the active form of the drug

Question 18

Effects on Inducers on Substrate? On prodrugs?

Answer 18

Inducers DECREASE the conc of Substrate, EXCEPT with Prodrugs

T4 Inducers increase the conc of active metabolite of prodrug

Question 19

Effects on Inhibitors on Substrate? On prodrugs?

Answer 19

Inhibitors INCREASE the conc of the substrate, EXCEPT prodrugs

T4 inhibitors decrease active metabolites of prodrugs

Question 20

About 25% of drugs go through CYP 2D6, including many?

Answer 20

Pain and Psychiatric drugs

Question 21

What are the practical considerations when d/c an inhibitor or inducer?

Answer 21

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

Question 22

Which has a “lag” time? Effect of the inhibition or Inducer?

Answer 22

Inducer: full effect may not be present for up to 2 wks. Similarly, it takes 2-4 wks for the induction to disappear completely

Question 23

What’s P-glycoproteins (P-gp)?

Answer 23

Efflux transporters found in the gut and other organs.

They pump drugs back into the gut (to exit out of the body)

Question 24

What happens if a drug is subject to efflux, and the transporter is inhibited by a different drug?

Answer 24

The substrate drug conc will INCREASE in the plasma

Question 25

What happens to blood levels of a drug, if an inducer is given that causes the production of more pumps?

Answer 25

The blood levels of the substrate will DECREASE

Question 26

What's P-gp inducer?

Answer 26

Causes the creation of more of the P-gp and blood levels go down

Question 27

Effect of P-gp on toxin?

Answer 27

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

Question 28

What's P-gp inhibitor?

Answer 28

Inhibits the drug-pump-inhibitor and consequently, blood levels of the drug increase

Question 29

List strong inhibitors of P-gp Efflux pump (results in increased in blood levels of the drug)

Answer 29

Itraconazole, Ketoconazole Verapamil Ritonavir; Lopinavir/Ritonavir; Indinavir/Ritonavir Conivaptan Clarithromycin; Eryhromycin Amiodarone Quinidine

Question 30

List strong inducers of P-gp Efflux pump (results in decreased in blood levels of the drug)

Answer 30

Rifampin Avasimibe Carbamazepine Phenytoin St. John's wort Tipranivir/Ritonavir

Question 31

List p-gp efflux pump substrates

Answer 31

Aliskiren Colchicine Dabigatran Cyclosporine Digoxin Fexofenadine Posaconazole Ranolazine Rivaroxaban Saxagliptin Tacrolimus

Question 32

Look at pg 192 for CYP 450 substrates, inducers and inhibitors

Answer 32

LOOK!

Question 33

List big inducers of CYP 450

Answer 33

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 ```

Question 34

List big inhibitors of CYP 450

Answer 34

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)

Question 35

Are all Macrolides big CYP inhibitors?

Answer 35

No! Azithromycin is NOT a big inhibitor of CYP

Question 36

Why's cimetidine most difficult H2RA to use?

Answer 36

Big CYP inhibitor Has androgen-blocking effects that can cause gynecomastia (swollen, or painful breast tissue or impotence)

Question 37

What meds must be reduced by 30-50% when starting Amiodarone?

Answer 37

Digoxin Warfarin Quinidine Procainamide Simvastatin, Lovastatin and Atorvastatin

Question 38

What drugs are most likely to be dosed with Amiodarone? Why?

Answer 38

Digoxin and Warfarin Bcuz they are used in HF and arrhythmias

Question 39

T/F? If warfarin or digoxin is on board first, the pharmacist must recognize the interaction and decrease the dose when amiodarone is started?

Answer 39

True

Question 40

What's medical conditions may cause an increase in digoxin levels?

Answer 40

Decline renal fxn Hypokalemia

Question 41

What other considerations (other than amiodarone mentioned previously) may be considered when digoxin is used?

Answer 41

Additive drugs that lower HR (< 60 BPM) Primarily beta-blockers and non-DHP CCBs (Diltazem and verapamil) Others include: Dexmedetomidine (Precedex), Clonidine and Opioids

Question 42

List drug interactions with grapefruit/ juice that are considered clinically significant

Answer 42

Rivaroxaban - there could be an increased bleeding risk Ticagrelor QT prolongers + grapefruit/ juice = risk of torsades Lurasidone Quinidine

Question 43

Effect of Lamotrigine + Valproate used concurrently

Answer 43

Increased risk of rash

Question 44

List drugs not to use MAOI with

Answer 44

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 ```

Question 45

Hydrocodone and Tramadol interaction?

Answer 45

Those on 2D6 inhibitors: Fluoxetine Paroxetine Others May be at increased risk of respiratory depression

Question 46

DI with codeine?

Answer 46

Codeine undergoes conversion to morphine by 2D6 enzyme

Question 47

DI with Oxycodone and Methadone?

Answer 47

Metabolized by 3A4

Question 48

PDE-5 inhibitors

Answer 48

3A4 substrate T4 avoid use with 3A4 inhibitor (inh metabolism leading to higher drug levels)

Question 49

Which meds have chelation risks?

Answer 49

Quinolones, Tetracyclines

Question 50

Which statins have the most risk of drug interaction?

Answer 50

LAS Lovastation, Atorvastatin, Simvastatin

Question 51

Which drugs increase statin drug levels?

Answer 51

Gemfibrozil Macrolides

Question 52

Which Calcineurin inhibitors are subject to significant rxn?

Answer 52

Tacrolimus and Cyclosporine

Question 53

List drugs that bleeding risk is a concern in

Answer 53

Anticoagulants (warfarin, Dabigatran, Rivaroxaban, heparin and others) AND Antiplatelets (aspirin, dipyridamole, Clopidogrel, prasugrel, ticagrelor)

Question 54

What dx condition may cause hyperkalemia risk?

Answer 54

Since potassium is renally cleared, severe renal dx causes hyperkalemia

Question 55

List drugs that should be avoided if potassium is high at baseline (> 5 mEq/L)

Answer 55

Spironolactone Eplerenone ``` ACEI ARBs Aliskiren Amiloride Triamterene Salt substitutes (KCL) Drospirenone-containing OCPs ```

Question 56

List substances that may result in CNS depression

Answer 56

``` Alcohol Most pain meds (ALL opioids, some NSAIDs, other pain meds) Skeletal muscle relaxants Anticonvulsants Benzodiazepines Barbiturates Hypnotics Mirtazapine Trazodone Dronabinol Nabilone Propranolol Clonidine ```

Question 57

List agents that may cuz QT prolongation and Torsades De Pointes

Answer 57

Mostly arrhythmia drugs and effect is additive

Question 58

List agents that may cuz Ototoxicity

Answer 58

``` Salicylates Vanco Aminoglycosides Cisplatin Loop diuretics ```

Question 59

Which meds can also increase INR?

Answer 59

Amiodarone Trimethoprim/Sulfamethoxazole (Bactrim) Ketoconazole

Question 60

What do u need to separate Cipro from?

Answer 60

Multivitamin Iron Yogurt, cheese

Question 61

What meds can increase risk of arrhythmias?

Answer 61

Fluconazole Erythromycin Ziprasidone

Question 62

Primary location of CYP enzymes?

Answer 62

Liver and Intestines