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GI Week 3 > ICL 8.3: Liver Dysfunction & Drug Interactions > Flashcards

ICL 8.3: Liver Dysfunction & Drug Interactions Flashcards

1
Q

what are CYP450 enzymes?

A

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.

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2
Q

what is a substrate?

A

chemical moiety that is target of metabolic enzymes

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3
Q

what are inducers?

A

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

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4
Q

what is an inhibitor?

A

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

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5
Q

what are auto-inducers?

A

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

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6
Q

what is first pass metabolism?

A

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!

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7
Q

what is oral bioavailability?

A

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

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8
Q

what is ADME?

A

a pharmacokinetic acronym that describes the disposition of drugs in the body

it stands for Absorption, Distribution, Metabolism and Excretion.

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9
Q

what is pharmacokinetics?

A

the study of the ADME of drugs in the body

Absorption, Distribution, Metabolism and Excretion

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10
Q

what is an active metabolite?

A

when a drug is transformed through metabolism into a pharmaceutically active entitt

example: morphine is an active metabolite of codeine

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11
Q

what is excretion?

A

the process by which drugs and their metabolites are eliminated from the body

the most common routes of excretion are urine and feces

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12
Q

what does it mean if a drug has a narrow therapeutic index?

A

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

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13
Q

what is the common mechanisms of interaction between drugs?

A

common mechanisms of drug interactions:

  1. enzyme induction/inhibition
  2. P-glycoprotein modification
  3. opposing mechanisms
  4. additive mechanisms, drug displacement from binding site
  5. 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
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14
Q

what does it mean if a drug interaction is concentration vs. dose dependent?

A

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

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15
Q

what does it mean if a drug interaction is contraindicated?

A

contraindicated drug interactions should be considered in the context of legal liability

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16
Q

what are some mitigation strategies to avoid bad drug interactions?

A
  1. if the combination is contraindicated, stop one or both agents
  2. reduce dose of impacted agent
  3. increase the dose of the impacted agent
  4. monitor the patient (symptoms or drug levels)
  5. find alternative agent
  6. educate the patient to watch for signs of toxicity or treatment failure
17
Q

what are some clinical pearls to consider for drug-drug interactions?

A
  1. drug interactions can happen over time, not always right away (particularly CYP interactions)
  2. can happen when starting a new med, STOPPING a med and with dose changes
  3. can make the drug less effective or more toxic
  4. can be used for therapeutic purposes
  5. cannot always be reliably predicted; they’re mpacted by pharmacogenomics, nutritional status etc.
18
Q

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?

A
  1. 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

  1. 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

19
Q

when you’re thinking about drug interactions, what 4 questions should you ask yourself?

A
  1. what real or potential drug interactions exist?
  2. what will happen in this DI?
  3. do you consider this DI serious?
  4. what potential solutions exist?
20
Q

which drugs are the substrates, inhibitors and inducers of CYP-3A4?

A

SUBSTRATE

  1. clarithromycin
  2. erythromycin
  3. alprazolam
  4. cyclosporine

INHIBITORS

  1. itraconazole
  2. erythromycin
  3. verapamil
  4. diltiazem
  5. cimetidine
  6. amiodarone

INDUCER

  1. carbemazepine
  2. phenobarbital
  3. phenytoin
  4. rifampin
  5. St. John’s Wort
21
Q

which drugs are the substrates, inhibitors and inducers of CYP-2C9?

A

SUBSTRATES

  1. diclofenac
  2. ibuprofen
  3. naproxen
  4. glipizide
  5. glyburide
  6. losartan
  7. celecoxib
  8. phenytoin
  9. valproic acid
  10. warfarin

INHIBITORS

  1. amiodarone
  2. fluconazole
  3. metronidazole
  4. paroxetine
  5. sulfamethoxazole

INDUCERS

  1. carbamazepine
  2. phenobarbital
  3. rifampin
  4. St. John’s Wort
22
Q

which drugs are the substrates, inhibitors and inducers of CYP-2D6?

A

SUBSTRATE

  1. carvedilol
  2. metoprolol
  3. amitriptyline
  4. fluoxetine
  5. paroxetine
  6. risperidone
  7. codeine
  8. oxycodone
  9. risperidone
  10. tamoxifen

INHIBITORS

  1. bupropion
  2. fluoxetine
  3. paroxetine
  4. duloxetine
  5. amiodarone
  6. cimetidine
  7. diphenhydramine

INDUCER
1. rifampin

23
Q

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
A
  1. phenobarbital and phenytoin are 3A4 inducers
  2. 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

24
Q

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

A

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

25
Q

what are the 2 staging systems used to evaluate liver disease severity?

A
  1. Child-Pugh
  2. 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.)

26
Q

what is the primary use of the Child-Pugh staging system?

A
  1. medication labeling
  2. dose adjustment
  3. HCV medication dosing
27
Q

what is the primary use of the MELD staging system?

A
  1. predict mortality

2. stratify for transplant priority

28
Q

how do you calculate the Child-Pugh score?

A
  1. encephalopathy
  2. ascites
  3. total bilirubin
  4. albumin
  5. INR

you get 1-3 points in each group and that puts you in class A,B or C = mild, mode or severe disease

29
Q

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?

A

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

30
Q

what are pharamcogenomics?

A

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

31
Q

what is an example of a drug that has a variance in CYP enzymes due to pharamcogenomics?

A

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

32
Q

what is an example of variance in drug target due to pharamcogenomics?

A

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

33
Q

what is the pharamcogenomic variance with the p=glycoprotein efflux pump?

A

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

34
Q

when do you do pharmacogenomic testing?

A
  1. cost vs. benefit
  2. availability of testing
  3. timeliness of results
35
Q

what is the criteria for the routine use of pharcogenetic testing?

A
  1. side effects that are significant and/or irreverisble
    ex. HIV medications like abacavir, efavirenz, atazanirvir
  2. 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
  3. the test is readily available
  4. other alternatives to the therapy are not ideal or available
  5. the test is cost effective

GI Week 3 (12 decks)

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