ICL 8.3: Liver Dysfunction & Drug Interactions Flashcards
what are CYP450 enzymes?
enzymes essential for the production of cholesterol, steroids, prostacyclins, and more
they are also necessary for the detoxification of foreign chemicals and the metabolism of drugs.
what is a substrate?
chemical moiety that is target of metabolic enzymes
what are inducers?
a drug that increases the activity of certain CYP enzymes thus increasing the rate of metabolism of substrate drugs
when you induce the metabolism, you increase the rate of metabolism of the drug and decrease the drug level
what is an inhibitor?
a drug that decreases the activity of certain CYP enzymes thus decreasing the rate of metabolism of substrate drugs
when you inhibit the metabolism you increase the drug level
what are auto-inducers?
a drug that is both an inducer and a substrate of the same CYP enzyme thus over time it induces it own metabolism
example: carbamazepine induces CYP3A4 and is also a substrate
what is first pass metabolism?
the concentration of an orally administered drug is significantly reduced before it reaches the circulation
example: Insulin; this is why you can’t give insulin orally!
what is oral bioavailability?
the percent of active drug that reaches the circulation when a drug is administered orally
the oral bioavailability of levothyroxine is around 40% but can be increased to ~80% when administered on an empty stomach
what is ADME?
a pharmacokinetic acronym that describes the disposition of drugs in the body
it stands for Absorption, Distribution, Metabolism and Excretion.
what is pharmacokinetics?
the study of the ADME of drugs in the body
Absorption, Distribution, Metabolism and Excretion
what is an active metabolite?
when a drug is transformed through metabolism into a pharmaceutically active entitt
example: morphine is an active metabolite of codeine
what is excretion?
the process by which drugs and their metabolites are eliminated from the body
the most common routes of excretion are urine and feces
what does it mean if a drug has a narrow therapeutic index?
a drug which has a narrow concentration window in which it is therapeutic
below the window and the drug is ineffective, above the window the drug produces toxic effect
example: warfarin
what is the common mechanisms of interaction between drugs?
common mechanisms of drug interactions:
- enzyme induction/inhibition
- P-glycoprotein modification
- opposing mechanisms
- additive mechanisms, drug displacement from binding site
- alterations in protein binding
ex. the interaction between sotalol and ondansetron is the additive mechanism on the QT Interval –> they both prolong the QT interval and when they’re given together it’s even worse
what does it mean if a drug interaction is concentration vs. dose dependent?
some interactions only occur when dosing thresholds are met or exceeded
ex. simvastatin and amlodipine interaction –> amlodipine can increase the serum concentration of simvastatin. This only becomes clinically significant at simvastatin doses >20mg
what does it mean if a drug interaction is contraindicated?
contraindicated drug interactions should be considered in the context of legal liability
what are some mitigation strategies to avoid bad drug interactions?
- if the combination is contraindicated, stop one or both agents
- reduce dose of impacted agent
- increase the dose of the impacted agent
- monitor the patient (symptoms or drug levels)
- find alternative agent
- educate the patient to watch for signs of toxicity or treatment failure
what are some clinical pearls to consider for drug-drug interactions?
- drug interactions can happen over time, not always right away (particularly CYP interactions)
- can happen when starting a new med, STOPPING a med and with dose changes
- can make the drug less effective or more toxic
- can be used for therapeutic purposes
- cannot always be reliably predicted; they’re mpacted by pharmacogenomics, nutritional status etc.
Age: 47
Sex: M
Weight:89kg
PMH: PKD s/p renal transplant 6 months ago HTN Hyperlipidemia Tobacco use insomnia
Medications: Cyclosporine 200mg twice daily Tacrolimus 5mg BID Atorvastatin 40mg daily Metoprolol XL 25mg once daily Fluoxetine 20mg daily St. John's Wort 2 caps twice daily Zolpidem PRN
what drug drug interactions are there and how would you fix them?
- cyclosporine is a 3A4 substrate
St. John’s Wort is a 3A4 inducer
this means there will be increased metabolism of cyclosporin which can result in rejection of transplant
this is a serious drug interaction!!! so you can either increase the dose of CSA, monitor CSA levels, change SJW, or change CSA….probably change the SHW
- metoprolol and fluoxetine are 2D6 substrates
fluoxetine is a 2D6 inhibitor
this means there will be decreased metabolism of metoprolol and increased metoprolol levels
possible outcomes include low BP, bradycardia, or heart block –> so look at the patients current BP and HR to decide if this is going to have bad effects; this probably isn’t clinically significant interaction due to the low dose of metoprolol –> so just educate the patient and monitor for symptoms
also fluoxetine is both an inhibitor and substrate2D6 so there could be decreased metabolism of fluoxetine and therefore increased levels –> this probably isn’t a serious interaction because it’s factored into the inherent nature of fluoxetine pharmacokinetics and doctors dose it in a certain way –> so just monitor for side effects
when you’re thinking about drug interactions, what 4 questions should you ask yourself?
- what real or potential drug interactions exist?
- what will happen in this DI?
- do you consider this DI serious?
- what potential solutions exist?
which drugs are the substrates, inhibitors and inducers of CYP-3A4?
SUBSTRATE
- clarithromycin
- erythromycin
- alprazolam
- cyclosporine
INHIBITORS
- itraconazole
- erythromycin
- verapamil
- diltiazem
- cimetidine
- amiodarone
INDUCER
- carbemazepine
- phenobarbital
- phenytoin
- rifampin
- St. John’s Wort
which drugs are the substrates, inhibitors and inducers of CYP-2C9?
SUBSTRATES
- diclofenac
- ibuprofen
- naproxen
- glipizide
- glyburide
- losartan
- celecoxib
- phenytoin
- valproic acid
- warfarin
INHIBITORS
- amiodarone
- fluconazole
- metronidazole
- paroxetine
- sulfamethoxazole
INDUCERS
- carbamazepine
- phenobarbital
- rifampin
- St. John’s Wort
which drugs are the substrates, inhibitors and inducers of CYP-2D6?
SUBSTRATE
- carvedilol
- metoprolol
- amitriptyline
- fluoxetine
- paroxetine
- risperidone
- codeine
- oxycodone
- risperidone
- tamoxifen
INHIBITORS
- bupropion
- fluoxetine
- paroxetine
- duloxetine
- amiodarone
- cimetidine
- diphenhydramine
INDUCER
1. rifampin
Age:39
Sex: Female
Weight:70kg
PMH:
MRDD
Seizure disorder
HTN
Medications: Phenytoin 100mg TID Phenobarbital 60mg once daily Levetiracetam 500mg BID Lisinopril 10mg once daily Chlorthalidone 25mg once daily
- phenobarbital and phenytoin are 3A4 inducers
- phenytoin is a 2C9 substrate and phenobarbital is 2C9 inducer
since phenobarbital is a 2C9 inducer and phenytoin is a substrate, this could result in increased metabolism of phenytoin and potentially increase seizure activity –> the severity of this DI depends on the temporal relationship between the 2 drugs –> you could stop the pneobarbitol, increase phenytoin or monitor phenytoin levels
phenobarbitol and phenytoin are both inducers of 3A4 so since you have double inducers, you have significant potential for DI with all the drugs
Age: 29
Sex: F
Weight: 68kg
PMH:
Headache
Vitamin D deficiency
Recurrent vaginal candidiasis
Medications:
Ibuprofen 400mg PRN HA
Egocalciferol 50,000 units once weekly x 8 weeks
Fluconazole 150mg daily for 10 days
ibuprofen is a 2C9 substrate while fluconazole is an inhibitor
this means there will be decreased metabolism of ibuprofen which increases its levels
severity of this DI depends on how much ibuprofen she uses? also the fluconazole is only for 10 days so you’re probably fine
but just educate the patient to limit ibuprofen while on fluconazole
what are the 2 staging systems used to evaluate liver disease severity?
- Child-Pugh
- model of end stage liver disease (MELD)
both rating systems examine the liver’s ability to synthesize (by measuring albumin and PT/INR) and to eliminate (levels of bilirubin)
both also use clinical markers and symptoms (encephalopathy, ascites, etc.)
what is the primary use of the Child-Pugh staging system?
- medication labeling
- dose adjustment
- HCV medication dosing
what is the primary use of the MELD staging system?
- predict mortality
2. stratify for transplant priority
how do you calculate the Child-Pugh score?
- encephalopathy
- ascites
- total bilirubin
- albumin
- INR
you get 1-3 points in each group and that puts you in class A,B or C = mild, mode or severe disease
Age: 58
Sex: Male
Weight: 110kg
PMH: CHF HTN Hyperlipidemia Alcoholic Cirrhosis Encephalopathy (mild) Ascites (diuretic responsive)
Medication List: Furosemide 40mg daily Spironolactone 100mg daily Lisinopril 40mg once daily Carvedilol 12.5mg BID Atorvastatin 80mg daily Lactulose 20g TID
Pertinent Labs: AST: 203 u/l (10-40 u/l) ALT: 176 u/l (7-56 u/l) INR: 1.4 (<1.0) Total Bili:2.8 mg/dl (0.1-1.2 mg/dl) Albumin: 29 g/l (35-55 g/l)
His cardiologist wishes to discontinue lisinopril and start Entresto (sacubitril/valsartan) for heart failure.
what is their Child-Paugh score?
encephalopathy = mild = 2
ascites = diuretic responsive = 2
total bilirubin = 2.8 = 2
albumin = 29 = 2
INR = 1.4 = 1
total = 9 = class B; moderate disease severity
class A = 5-6 class B = 7-9 class C = 10-15
use of entresto isn’t recommended in class C patients so since he’s at the upper limit of class B, keep an eye on him and his dosing
what are pharamcogenomics?
the study of how a person’s genes effect their response to drugs
ex. variance in CYP enzymes and other metabolic pathways, variance in drug target, or other variances resulting in changes in ADME drug properties
alterations could lead to more or less drug efficacy or more/less drug side effects
what is an example of a drug that has a variance in CYP enzymes due to pharamcogenomics?
clopidogrel
CPY2C19*2 are poor metabolizers of clopidogrel –> low clopidogrel activity because they won’t convert CLP to its active form and it would have less efficacy = stroke, stent rethrombosis, etc.
CYP2C19*17 are high metabolizers of clopidogrel –> they would convert more CLOP to the active form than usual which could result in increased bleeding risk
***clopidogrel is a prodrug that gets converted to an active metabolite which is responsible for its pharmacologic activity
what is an example of variance in drug target due to pharamcogenomics?
Epidermal Growth Factor Receptor positive colon cancers respond to EGFR-Tyrosine Kinase Inhibitors (TKI’s) but non-EGFR+ do not respond to treatment
so based on someones genetics, they may or may not respond to a certain drug
what is the pharamcogenomic variance with the p=glycoprotein efflux pump?
the p-glycoprotein efflux pump is responsible for pumping drug out of tissues and into locations where they can be more readily excreted or metabolized like in the kidney tubules, intestinal lumen etc.
certain mutations in P-Gp make the pump more or less active which increases or decreases exposure to drugs that are P-Gp substrate
ex. digoxin, colchicine
p-glycoprotein mutation makes their pump more active, they’ll have a less than expected response to digoxin – if their pump is less active, they could have toxic symptoms of digoxin at doses that seem to be in the therapeutic range
when do you do pharmacogenomic testing?
- cost vs. benefit
- availability of testing
- timeliness of results
what is the criteria for the routine use of pharcogenetic testing?
- side effects that are significant and/or irreverisble
ex. HIV medications like abacavir, efavirenz, atazanirvir - patient response to treatment is essential and timely –> if you don’t pick the right drug based on the patients pharmacogenomics, you could waste prevcious time using a drug that isn’t effective
ex. EGFR-TKI for colon cancer, HER-2 positive breast cancers, Philadelphia Chromosome for CML - the test is readily available
- other alternatives to the therapy are not ideal or available
- the test is cost effective
