Learning Drug Interactions

Question 1

What is pharmacodynamics (PD)?

Answer 1

the effect or change that a drug has on some type of organism, such as the human body

Question 2

When does a pharmacodynamic drug interaction occuR?

Answer 2

when two or more drugs are given together, and their end effects impact each other

Question 3

What kind of effect occurs when multiple drugs that are agonists at the same receptor are taken together?

Answer 3

additive effect

Question 4

What do antagonists block the action of?

Answer 4

agonists

Question 5

What kind of effect occurs when drugs that have similar end effects through different mechanisms/receptors are taken together?

Answer 5

additive effect

Question 6

What is the risk with concurrent use of benzodiazepines and opioids?

Answer 6

results in profound sedation, respiratory depression, coma and death

Question 7

When is synergism present?

Answer 7

when the effect from two drugs taken in combination is greater than the effect from simply adding the two individual effects together

Question 8

What is pharmacokinetics (PK)?

Answer 8

The effect the body has on drugs as it goes through ADME [absorption (typically in small intestine); distribution (mainly in blood dispersed through tissues); metabolism (including enzymatic reactions); excretion (removal of drug or metabolites (end products) from the body)]

Question 9

When do PK drug interactions occur?

Answer 9

when one drug alters the absorption, distribution, metabolism or excretion of another drug

Question 10

When does chelation occur?

Answer 10

when a drug binds to polyvalent cations (Mg, Ca, Fe) in another compound

Question 11

What medications should be separated from polyvalent cations or other binding properties?

Answer 11

Quinalones, tetracyclines, levothyroxine, oral bisphosphonates

Question 12

Some medications require an acidic gut for adequate absorption, what happens if the gastrointestinal pH is increased for these medications?

Answer 12

absorption will be decreased

Question 13

When do the majority of PK drug interactions occur?

Answer 13

during metabolism in the liver

Question 14

What is the primary route of drug excretion?

Answer 14

renal excretion

Question 15

What is the purpose of cytochrome P450 enzymes (CYP450)?

Answer 15

to catalyze rxns that either produce essential compounds (ex. cholesterol and cortisol) or uncover or insert a polar group on a compound to facilitate (aka make easier) renal excretion.

Question 16

where are CYP450 enzymes primarily expressed?

Answer 16

in the liver

Question 17

What CYP enzyme metabolizes ~34% of all CYP450-metabolized drugs?

Answer 17

CYP3A4

Question 18

What effects the function of CYP enzymes?

Answer 18

genetics and other drugs that act as enzyme inhibitors or inducers

Question 19

How do prodrugs become their active form?

Answer 19

taken in an inactive form and are converted by CYP450 enzymes into the active form

Question 20

What do drug manufacturers use prodrugs?

Answer 20

to extend dosing intervals and prevent drug abuse

Question 21

Are CYP450 enzymes phase I or II enzymes?

Answer 21

phase I

Question 22

Is N-acetyltransferase (NAT) a phase I or II enzyme?

Answer 22

phase II

Question 23

T/F: NATs are highly polymorphic

Answer 23

true

Question 24

What happens if drugs are CYP enzyme inhibitors with substrates for the same CYP enzyme?

Answer 24

they decrease enzyme function and the ability to metabolize compounds, leading to substrates for the same CYP enzyme to have a decreased rate of drug metabolism and an increased serum drug level

Question 25

What happens if drugs are CYP enzyme inhibitors with prodrugs?

Answer 25

the active drug concentration decreases with an inhibitor because there are less functional enzymes to convert the prodrug to the active form

Question 26

Is enzyme inhibition fast or slow?

Answer 26

fast; effects are seen within a few days and will end quickly when the inhibitor is discontinued

Question 27

What are the major CYP inhibitors?

Answer 27

G loves PACMAN: 
Grapefruit 
Protease inhibitors (PI's) 
Azole antifungals 
Cyclosporine, cimetidine, cobicistat 
Macrolides (NOT azithromycin)
Amiodarone and dronedarone 
Non-DHP CCB (diltiazem and verapamil)

Question 28

What happens if major CYP inducers are used with substrates for the same CYP enzyme?

Answer 28

inducers increase enzyme production or activity, causing the substrates to have an increased rate of metabolism and a decreased serum level. in some cases causing therapeutic failure

Question 29

What happens if major CYP inducers are used with prodrugs?

Answer 29

the active drug concentration increases because there are more enzymes to catalyze the conversion to the active drug

Question 30

What are the major CYP inducers?

Answer 30

PS PORCS
Phenytoin 
Smoking 
Phenobarbital 
Oxcarbazepine and eslicarbazepine 
Rifampin and rifabutin, rifapentine 
Carbamazepine 
St. John's Wort

Question 31

Is CYP enzyme induction fast or slow?

Answer 31

slow; the full effect on drug levels may not be seen for up to 4 weeks and when the inducer is stopped may take 2-4 weeks for the induction effects to disappear completely

Question 32

What do permeability glycoprotein (P-gp) efflux pumps do?

Answer 32

located in many tissue membranes where they provide protection against foreign substances by moving them out of critical areas

Question 33

What do p-gp efflux pumps do in the cell membranes of the GI tract?

Answer 33

transport drugs and their metabolites out of the body by pumping them into the gut, where they can be excreted in the stool

Question 34

what happens when a drug blocks or inhibits p-gp to a drug that is a p-gp substrate?

Answer 34

the substrate will have increased absorption (less drug pumped into the gut) and the substrate level will increase

Question 35

What are common p-gp substrates?

Answer 35

anticoagulants (apixaban, rivaroxaban)
cardiovascular drugs (diltiazem, digoxin, verapamil, carvedilol)
immunosuppressants (cyclosporine, tacrolimus)
HCV (ombitasvir, paritaprevir, dasabuvir)
colchicine

Question 36

What are common p-gp inducers?

Answer 36

carbamazepine, phenobarbital, phenytoin, rifampin, st. johns wort

Question 37

What are common p-gp inhibitors?

Answer 37

anti-infectives (clarithromycin, itraconazole, posaconazole)
cardiovascular drugs (amiodarone, diltiazem, verapamil)
HIV drugs
HCV drugs
cyclosporine

Question 38

What can happen to a drug after it has been metabolized in the liver (aka enterohepatic recycling)?

Answer 38

after being metabolized in the liver, it can be transported back to the gut through bile. Once in the gut it can be reabsorbed (mainly in the small intestine), into the portal vein, and back to the liver

Question 39

What does enterohepatic recycling do to a drugs duration of action?

Answer 39

increases the duration of action

Question 40

What is the risk with amiodarone + warfarin (dronedarone has a similar interaction)?

Answer 40

amiodarone inhibits multiple enzymes including CYP2C9, which metabolizes the major warfarin isomer leading to decreased warfarin metabolism causing an increase in the INR and bleeding risk

Question 41

What action can be made by the pharmacist for when someone is taking amiodarone + warfarin?

Answer 41

if using amiodarone 1st and adding warfarin: start warfarin at a lower dose of = 5 mg.
if using warfarin 1st and adding amiodarone: decrease warfarin dose by 30-50%, depending on the INR
Taking both: make sure to monitor the INR and modify when needed

Question 42

What is the risk with amiodarone + digoxin?

Answer 42

amiodarone inhibits p-gp, where digoxin is a p-gp substrate. this leads to decreased digoxin excretion and increased ADRs/toxicity (decreased HR, increased risk of bradycardia, arrhythmia, and fatality)

Question 43

What actions can be made by the pharmacist for when someone is taking amiodarone + digoxin?

Answer 43

if using amiodarone 1st and adding digoxin: start oral digoxin at a low dose, such as 0.125 instead of 0.25 daily
if using digoxin 1st and adding amiodarone: decrease oral digoxin dose by 50%
Taking both amiodarone and digoxin: instruct pt to monitor for signs of dig toxicity (nausea, anorexia; if present check HR & contact prescriber); monitor HR (norm is 60-100); if dig is being used for rate control suggest the use of beta-blockers or non-DHP CCB

Question 44

What is the risk of loop diuretics + digoxin?

Answer 44

digoxin is cleared by p-gp and excreted by the kidneys, renal impairment can increase digoxin levels and toxicity. loops decrease K, Mg, Ca, and Na and low K, Mg or Ca will worsen arrhythmias. Digoxin toxicity is increased with low K and Mg levels and increased Ca levels

Question 45

What actions can be made by the pharmacist for when someone is taking a loop diuretic + digoxin?

Answer 45

monitor electrolytes & correct if abnormal; if the patient has renal impairment decrease digoxin dose or frequency, or discontinue

Question 46

What happens if someone takes multiple drugs that decrease heart rate (ex. diltiazem/verapamil or beta-blockers for rate contro; clonidine and beta-blockers for HTN)

Answer 46

additive effects when drugs that decrease HR are used together, including amiodarone, digoxin, beta-blockers, clonidine

Question 47

What actions can be made by the pharmacist for when someone is taking multiple drugs that decrease heart rate?

Answer 47

monitor HR (normal is 60-100)

Question 48

What is the risk of statins (simvastatin, lovastatin, atorvastatin) + strong CYP3A4 inhibitors?

Answer 48

increased levels of lovastatin, simvastatin and atorvastatin leading to an increased myopathy risk. which if severe can cause rhabdomyolysis with acute renal failure

Question 49

What actions can be made by the pharmacist for when someone is taking simvastatin/lovastatin/atorvastatin +strong CYP3A4 inhibitors?

Answer 49

simvastatin and lovastatin are contraindicated. recommend a statin not metabolized by CYP450 (pravastatin, rosuvastatin, pitavastatin)

Question 50

What is the risk of warfarin + CYP2C9 inhibitors or inducers?

Answer 50

inhibitors will increase levels of warfarin and increase INR and bleeding risk
inducers will decrease levels of warfarin and increase clotting risk

Question 51

What actions can be made by the pharmacist for when someone is taking warfarin + CYP2C9 inhibitors or inducers?

Answer 51

monitor INR