Drug Drug Interaction Flashcards
Drugs can interact with
Other drugs
Disease states mean they can make the disease worse
Food and drinks
Alcohol
What is a drug-drug interaction (DDI)?
Whenever one drug affects the pharmacokinetics, pharmacodynamics, efficacy, or toxicity of another drug
Object drug
Drug that is affected by the interaction
Precipitant drug
Drug causing the interaction
Antagonistic
One drug lessens the effects of another
Additive
Both drugs result in an increased effect means (two drugs result in an increase effect)
Synergistic
Both drugs result in an increased effect more than just the addition of both (4+4 =10)
Idiosyncratic
Response is unexpected from the known effects of either agent
Mechanisms of drug interactions Pharmacodynamic and Pharmacokinetic
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
Pharmacodynamic interactions of additive effects are
Additive anticholinergic effects
ACE-I and spironolactone
Combinations of drugs that prolong the QT interval on ECG
Pharmacodynamic interactions of antagonistic effects are
NSAID inhibiting antihypertensive effect of ACE-I
Pharmacokinetic: Absorption are
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)
Common precipitants are
Binding agents (cholestyramine, colestipol)
Cations (aluminum, magnesium, iron)
Altered stomach pH
Cautions are Rate vs. extent
Pharmacokinetic: Distribution
In distribution the most important plasma proteins are
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)
Pharmacokinetics: Metabolism
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)
The importance of P450 as protein is
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)
P450 activity can be inhibited by
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
P450 activity can be induced
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
P450 can exhibit genetic polymorphism Derived from longstanding clinical observations that capacity to metabolize drugs vary among racial groups
EM
PM
UM
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.
P450 role in human drug metabolism and important p-450 are
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
P450 isozyme factoids are
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)
P450 analyses are important in evaluating the potential for pharmacokinetic drug-drug interactions because
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
Object drug = _______
Precipitant drug = ______
Substrate
Inhibitor or inducer
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:
◼ Multiple pathways
◼ Differences in binding affinities
◼ Relative importance of each pathway
Complex metabolic pathways are when drugs metabolize by
all enzymes such as 1A2,2D6 and 3A4 which leads to less drug-drug interaction
Complex metabolic pathways are when drugs metabolize by only one enzyme
Cause more drug-drug interaction (because other drugs compete for that enzyme too)
P-glycoprotein (P-gp) is a
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)
P-gp in the gut leads to
Drug molecules pass through enterocytes to get into the systemic circulation
P-gp transports drug back into the gut lumen preventing systemic absorption
P-gp inhibition will result in
Increased bioavailability & drug effect
P-GP induction will result in
Decreased bioavailability & drug effect
Normal activity of P-gp efflux will bring
substrate into lumen to decrease absorption
Inhibition of normal P-pg efflux will bring drug
into plasma leads to increase drug absorption
P-gp in the liver and kidney
P-gp acts to increase the excretion of drugs by transporting molecules into bile and urine
P-gp inhibition in the liver and kidney will result in
Decrease metabolism/excretion
Increase drug effect
P-gp induction in the liver and kidney will result in
Increase metabolism/excretion
Decrease drug effect
Other drug metabolizing enzymes are
Flavin monooxygenases [Phase I]
P-glycoproteins [transporter function]
Uridine 5’-diphosphate glucuronosyl-transferases (UGTs) [Phase II]
Be Alert for Patients that are Vulnerable
Patients with new medications, dosage changes, or recent health change
Older patients
Polypharmacy
Be Alert for Drugs Involved in Clinically Significant Interactions
Drugs that are strong inhibitors or inducers of drug-metabolizing enzymes or transporters
Clarithromycin
Carbamazepine
Drugs with serious dose-dependent adverse effects or narrow therapeutic index drugs
Statins, CCB, methotrexate, oral anticoagulants, antipsychotics, opioids,
The overall strategy for DDI
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
Difference between Lexi comp and micro medex
Lexi comp tell us about the Risk Rating of drug
Micromedex tell us about Onset of the drug
Hansten & Horn’s Top 100 management strategies are
Class 1 – avoid combination
Class 2 – usually avoid combination
Class 3 – minimize risk
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
Decreases/increased
Increases/decreased
