Drug Drug Interaction

Question 1

Drugs can interact with

Answer 1

Other drugs
Disease states mean they can make the disease worse
Food and drinks
Alcohol

Question 2

What is a drug-drug interaction (DDI)?

Answer 2

Whenever one drug affects the pharmacokinetics, pharmacodynamics, efficacy, or toxicity of another drug

Question 3

Object drug

Answer 3

Drug that is affected by the interaction

Question 4

Precipitant drug

Answer 4

Drug causing the interaction

Question 5

Antagonistic

Answer 5

One drug lessens the effects of another

Question 6

Additive

Answer 6

Both drugs result in an increased effect means (two drugs result in an increase effect)

Question 7

Synergistic

Answer 7

Both drugs result in an increased effect more than just the addition of both (4+4 =10)

Question 8

Idiosyncratic

Answer 8

Response is unexpected from the known effects of either agent

Question 9

Mechanisms of drug interactions Pharmacodynamic and Pharmacokinetic

Answer 9

Pharmacodynamic
One drug induces a change in a patient’s response to a drug without altering the object drug’s pharmacokinetics.

Pharmacokinetic
One drug alters the rate or extent of absorption, distribution, metabolism, or excretion of another drug

Question 10

Pharmacodynamic interactions of additive effects are

Answer 10

Additive anticholinergic effects
ACE-I and spironolactone
Combinations of drugs that prolong the QT interval on ECG

Question 11

Pharmacodynamic interactions of antagonistic effects are

Answer 11

NSAID inhibiting antihypertensive effect of ACE-I

Question 12

Pharmacokinetic: Absorption are

Answer 12

Inhibition:
Precipitant drug impairs bioavailability of object drug resulting in the decreased therapeutic effect of the object drug ( means precipitant drug effect the ability of object drug leads to decrease in therapeutic window)

Question 13

Common precipitants are

Answer 13

Binding agents (cholestyramine, colestipol)
Cations (aluminum, magnesium, iron)
Altered stomach pH

Cautions are Rate vs. extent

Question 14

Pharmacokinetic: Distribution

In distribution the most important plasma proteins are

Answer 14

Albumin
Alpha-1-acid glycoprotein
lipoproteins

Displacement of highly protein-bound drugs ( drug reactions lead to displacing of the drug means more drug is available and INR will go up)

Question 15

Pharmacokinetics: Metabolism

Answer 15

In metabolism, Drugs are metabolized primarily in the liver to convert relatively nonpolar compounds to polar ones that can then be excreted
◼ Phase I reactions –> Oxidation (cytochrome P450)
◼ Phase II reactions –> Conjugation (glucuronidation, sulfation)

Question 16

The importance of P450 as protein is

Answer 16

The specificity of a chemical reaction is dictated by the protein environment around the active site
Cell proteins are expressed via genetic control
Pharmacogenetics: Implications for nomenclature and polymorphism effects on drug metabolism (means how different people show different enzymes)

Question 17

P450 activity can be inhibited by

Answer 17

Drugs metabolized by a common P450 will be competing for or sharing metabolic sites
A drug’s relative affinity for binding to the enzyme may influence the direction of the inhibition
Drugs that inhibit P450 may slow down its inherent activity or prevent the metabolism of other drugs at the site of action

Question 18

P450 activity can be induced

Answer 18

The drug can be metabolized faster and increase the number of metabolites.
Exogenous compounds can stimulate the synthesis of more P450 (as opposed to stimulation of activity)
More drugs can be metabolized → means decreased amounts of parent drug and increased amounts of metabolites formed

Question 19

P450 can exhibit genetic polymorphism Derived from longstanding clinical observations that capacity to metabolize drugs vary among racial groups
EM
PM
UM

Answer 19

Those with the average “wild type” alleles are called extensive metabolizers (EM)
Those with non-functional or missing alleles are called poor metabolizers (PM)
Those with alleles with repeated gene copies are called ultra-rapid metabolizers(UM)

Important note:
Co-administration of P450 inhibitors may “convert” EMs to PMs’’

Example: Middle eastern women will have ultra-rapid metabolizers so we need to give them more dose or dose them more frequently.

Question 20

P450 role in human drug metabolism and important p-450 are

Answer 20

At least 40 P450 enzymes are found in humans
Six P450 enzymes responsible for about 90% of all drug metabolism 1A2, 2C9, 2C19, 2D6, 2E1, 3A4
Minor but clinically relevant P450s 2A6, 2B6, 2C8
Found on smooth ER of hepatocytes, luminal epithelium of small intestine, other tissues

Question 21

P450 isozyme factoids are

Answer 21

Approx. % of total P450 Inducible? Genetic polymorphism?
1A2 10-15 Yes Yes
2C9/2C19 ~20 Yes Yes
2D6 ~1.5 No Yes
3A4 ~30 Yes (may have a close functional relationship with P-GP)

Question 22

P450 analyses are important in evaluating the potential for pharmacokinetic drug-drug interactions because

Answer 22

The use of multiple medications is becoming more commonplace
Most drugs are common substrates(i.e., a compound converted by an enzyme to a metabolic product) of P450 metabolism, and maybe therefore susceptible to P450-mediated reactions

Question 23

Object drug = _______

Precipitant drug = ______

Answer 23

Substrate

Inhibitor or inducer

Question 24

Metabolic pathway considerations
The simplest analysis can only consider interactions involving two drugs [A g B via CYPnXm]
The following influences must be factored in:

Answer 24

◼ Multiple pathways
◼ Differences in binding affinities
◼ Relative importance of each pathway

Question 25

Complex metabolic pathways are when drugs metabolize by

Answer 25

all enzymes such as 1A2,2D6 and 3A4 which leads to less drug-drug interaction

Question 26

Complex metabolic pathways are when drugs metabolize by only one enzyme

Answer 26

Cause more drug-drug interaction (because other drugs compete for that enzyme too)

Question 27

P-glycoprotein (P-gp) is a

Answer 27

ATP-binding cassette (ABC) transport protein Transports drug molecules out of cells Found in epithelial cells of intestines (enterocytes), liver, and kidney The net effect of P-gp is a decrease of drug in the systemic circulation ( it try to send stuff out of the circulation) (send it to intestinal lumen)

Question 28

P-gp in the gut leads to

Answer 28

Drug molecules pass through enterocytes to get into the systemic circulation P-gp transports drug back into the gut lumen preventing systemic absorption

Question 29

P-gp inhibition will result in

Answer 29

Increased bioavailability & drug effect

Question 30

P-GP induction will result in

Answer 30

Decreased bioavailability & drug effect

Question 31

Normal activity of P-gp efflux will bring

Answer 31

substrate into lumen to decrease absorption

Question 32

Inhibition of normal P-pg efflux will bring drug

Answer 32

into plasma leads to increase drug absorption

Question 33

P-gp in the liver and kidney

Answer 33

P-gp acts to increase the excretion of drugs by transporting molecules into bile and urine

Question 34

P-gp inhibition in the liver and kidney will result in

Answer 34

Decrease metabolism/excretion | Increase drug effect

Question 35

P-gp induction in the liver and kidney will result in

Answer 35

Increase metabolism/excretion | Decrease drug effect

Question 36

Other drug metabolizing enzymes are

Answer 36

Flavin monooxygenases [Phase I] P-glycoproteins [transporter function] Uridine 5’-diphosphate glucuronosyl-transferases (UGTs) [Phase II]

Question 37

Be Alert for Patients that are Vulnerable

Answer 37

Patients with new medications, dosage changes, or recent health change Older patients Polypharmacy

Question 38

Be Alert for Drugs Involved in Clinically Significant Interactions Drugs that are strong inhibitors or inducers of drug-metabolizing enzymes or transporters

Answer 38

Clarithromycin | Carbamazepine

Question 39

Drugs with serious dose-dependent adverse effects or narrow therapeutic index drugs

Answer 39

Statins, CCB, methotrexate, oral anticoagulants, antipsychotics, opioids,

Question 40

The overall strategy for DDI

Answer 40

Develop a systematic approach Useful for scanning entire patient medication list SUCH as micro medex, Lexi comp Useful for overviews of individual interactions such as Drug Interaction Facts and Hansten & Horn’s Top 100 Drug Interactions

Question 41

Difference between Lexi comp and micro medex

Answer 41

Lexi comp tell us about the Risk Rating of drug | Micromedex tell us about Onset of the drug

Question 42

Hansten & Horn’s Top 100 management strategies are

Answer 42

Class 1 – avoid combination Class 2 – usually avoid combination Class 3 – minimize risk

Question 43

Fill in the blanks: An inhibitor _________ the metabolism of a substrate, resulting in a(n) _________ level or effect of the substrate An inducer _________ the metabolism of a substrate, resulting in a(n) _________ level or effect of the substrate

Answer 43

Decreases/increased Increases/decreased