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Drug-induced liver injury Flashcards

1
Q

Only a minority of drugs have a predictable dose-dependent injury called

A

direct hepatotoxic drug reactions

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2
Q

Most DILI occurs unpredictably called _____, and not dependently entirely on the dose of the drug

A

idiosyncratic drug reactions

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3
Q

Usually the drug metabolism in the liver involves the conversion of _____/_____ compound which is difficult to excrete

A

hydrophobic lipophilic

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4
Q

The reactions that are performed by the liver enzymes can be described as ___ and ____ biotransformation reaction

A

phase 1

phase 2

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5
Q

this reaction involves oxidation of cytochrome p450 enzyme

A

Phase

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6
Q

this reaction involves the conjugation of drug itself or metabolites from phase 1 to the polar ligands such as sulfate, glutathione or glucorinic acid

A

Phase2

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7
Q

Phase one oxidative reaction convert the mildly toxic drug into ___ ____ ___ bc these oxidation reactions make the chemicals very reactive

A

highly toxic intermediate METABOLITE

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8
Q

In some case the phase 2 products can be also ___ toxic

A

highly

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9
Q

when the conjugation system is saturated or impaired highly toxic, highly reactive intermediates from phase one oxidation can ___, react with the cellular structure, and cause cellular damage.

A

accumulate

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10
Q

Drugs causes liver injury by 4 pathological mechanisms

A

Hepatocellular or cytotoxic injury
Cholestasis
Neoplasms
Vascular injury

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11
Q

this pathophysiologic mechanism, the drug has a direct toxic affect on the liver cells and causes the hepatocytes necrosis/apoptosis.

A

Hepatocellular or cytotoxic injury

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12
Q

this pathophysiologic mechanism many drugs interfere with normal bile flow from the liver. Drugs inhibit the transports on the canaliculus membrane and end up accumulating bile causing bile duct injury

A

Cholestasis

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13
Q

some drugs that cause Hepatocellular or cytotoxic injury (direct affect on liver cells causing necrosis/apoptosis)
are

A 
ACE inhibitors
acetaminophen
beta-blockers
proton pump inhibitors 
statins
amoxicillin
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14
Q

some drugs that cause that result in cholestasis (interfere with normal bile flow of liver) are

A 
ACE inhibitors
amoxicillin
infliximab
mesalamine
sex steroids
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15
Q

drugs that cause vascular injury are

A

Contraceptive steroids, anabolic steroids

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16
Q

this pathophysiologic mechanism leads to hepatic vein thrombosis, peliosis hepatis

A

Vascular injury

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17
Q

some drugs that cause that lead to neoplasms

A

Anabolic steroids

sex steroids

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18
Q

Many drugs interfere with the ____ at the cellular membrane causing membrane blebbing, rupture, cell lyses

A

cytoskeleton

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19
Q

Some drugs bind to the cellular protein like the heme contain portion of the cyt p450 enzymes, creating a nonfunctional enyme complexes also known as

A

adduct

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20
Q

can travel to the cell surface in vesicles and at the cellular membrane can serve as a target immunogen, which induces the attack by the tcell which in turn causes the production of various pro-apoptotic and pro-inflammatory cytokines

A

adduct

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21
Q

The central pro-inflammatory cytokines in TNFalpha and a pro-apoptic molecule is called

A

FAS ligand

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22
Q

Many drugs interfere with the ____ function which can cause accumulation of the ROS, innate damage, cellular death and the subsequent liver agents

A

mitochondrial

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23
Q

many agents are known to inhibit the transporters on the _____ membrane and interfere with the normal export of bile components into the bile canaliculus causing accumulation in the hepatocytes which lead to hepatocyte injury and liver damage

A

canaliculus

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24
Q

some mechanisms of DILI - drug induced liver injury are:

A
  • inhibiting the transporters on the canaliculus membrane
  • interfering with mitochondrial function
  • binding to cellular proteins creating non-functional enzyme complex
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25
previous, the max dose for acetaminophen was _____. today the suggested dose is ____
3900-4000mg | 3000-3250mg
26
Exceeding the maximum recommended dose of acetaminophen, which is ___ g per day, can cause serious liver injury
4
27
> ___ of the cases of acute liver failure in the US are due to APAP (acetaminophen)
1/3
28
between 1998 to 2008, _____, which is ACETAMINOPHEN was THE LEADING CAUSE DILI
PARACETAMOL
29
90% OF ACETAMINOPHEN IS CONJUGATED TO _____ OR ____ AND PRODUCES NOT TOXIC METABOLITES WHICH CAN BE EXCRETED IN THE URINE HOWEVER ABOUT 5-10% IS DIRECTEDTO THE CTYOCHROME P450 OXIDASE SYSTEM WHICH IS HIGHLY TOXIC AND HIGHLY REACTIVE INTERMEDIATE CALLED _____, AND CAN ACT AS AN ELECTROPHILE OR OXIDIZE.
SULFATE GLUCURONIDE N ACETYL-P-BENSOQUINOEIMINE (NAPQI)
30
IF ACETAMENOPHIN IS INJECTED AT NORMAL DOSES, ITS RAPIDLY CONJUGATED TO INTRACELLULAR ___, WHICH PRODUCES UNTOXIC METABOLITES HOWEVER, IF ACETOMENOPHIN IS ADMIN AT OVERDOSE LEVEL, IT SATURATES THE CONJUGATION OF ENZYMES SO MORE ACETOMENOPHIN IS SHUNTED TOWARDS THE ____, WHICH RESULTS IN THE INCREASE OF NAPQI (HIGHLY TOXIC)
GLUTATHIONE | CYTOCHROME P450 OXIDATION SYSTEM
31
THIS CAUSES THE DEPLETION OF INTRACELLULAR GLUTATHIONE
NAPQI
32
WHEN THERE'S NO GLUTATHIONE AVAILABLE TO CONJUGATE NAPQI, IT STARTS TO ACCUMULATE WITHIN THE CELLS AND HAS THE ABILITY TO BIND TO ___ PROTEINS AND CHANGE THE PROTEIN AND DNA STRUCTURE CAUSING A LOT OF CYTOTOXIC EFFECTS
CYSTEINE
33
NAPQI CAN CAUSE THE FOLLOWING EFFECTS:
``` Mitochondrial destruction loss of ATP Altered calcium homeostasis DNA damage intracellular protein modification ```
34
______ is a highly reactive two-electron moiety that can act as an electrophile or oxidant
NAPQI
35
VARIOUS DRUG AND AGENTS ACTIVATE THE CYTOCHROME P450 OXIDATION SYSTEM. MOST COMMON DRUGS ARE: __ THEREFORE, THEY INCREASE NAPQI PRODUCTION AND SHOULD NOT BE ADMINISTERED WITH ACETAMINOPHEN
RIFAMPIN PHENOLBARBITOL PHENYTOIN CARBAMAZEPINE
36
____ IMMUNE SYSTEM IS AN IMPORTANT MODULATOR OF THE FINAL OUTCOME OF THE ACETOMENOPHEN INDUCED LIVER DAMAGE
INNATE
37
THE LIVER ____ CELLS AND KILLER _____ CAN RECOGNIZE THE NAPQI DAMAGE HEPATOCYTES AND CAUSE THE RELEASE OF INJUROUS CYTOKINES ALONG WITH PROTECTIVE FACTORS
KUPFFER TCELLS NK
38
____ AND ___ FACTORS DETERMINE WHETHER THE PERSISTANT INFLAMMATION AND APOTOSIS WILL OCCUR OR IF IT WILL RESULT IN MILD INJURY AND HEPATOCYTES RECOVERY
INJURIOUS | PROTECTIVE
39
EXAMPLES OF PROTECTIVE CYTOKINES ARE:
INTERLEUKINS 6 & 10
40
INJURIOUS CYTOKINES ARE:
FASL IFNy TNF
41
THE ANTIDOTE FOR ACETAMINOPHEN INDUCED LIVER DAMAGE AND ACTEOMINOPHEN OVER DOSE IS
N-ACETYLCYSTEINE
42
FUNCTIONS OF N-ACETYLCYSTEINE | ARE:
-INCREASE GLUTATHIONE CONCENTRATION ENHANCE SULFATE CONJUGATION - ACTS AS ANTI-INFLAMMATORY/ANTIOXIDANT - INCREASE NO CONC AND PROMOTE BLOOD FLOW
43
IF ADMINISTERED WITHIN 8 HOURS, IT WILL RESULT IN THE MAXIMUM HEPATO-PROTECTIVE EFFECT FOR ACUTE ACETAMINOPHEN INGESTION
N-ACETYLCYSTEINE
44
AN AGENT WHICH CAN INDUCE AN IMMUNE RESPONSE ONLY IF ITS BOUND TO CARRIER SUCH AS CELLULAR PROTEIN
HAPTEN
45
THIS HYPOTHESIS ASSUMES THAT VARIOUS DRUGS AND MOST COMMON REACTIVE METABOLITES OF THE DRUG CAN COVALENTLY BIND TO THE CELLULAR PROTEINS RESULTING IN HAPTENIZATION AND FORMATION IMMUNOGENIC DRUG PROTEIN COMPLEX. THIS RESULTS IN MHC2 PRESENTATION, DEVELOPMENT OF CYTOTOXIC TCELL ATTACK ON THE HEPATOCYTES DISPLAYING HAPTENIZED PEPTIDES OR MHC 1 PRESENTATION ON THEIR CELL SURFACE IN ADDITION IT CAUSES THE PRODUCTION OF ANTIBODIES WHICH TARGET THE HAPTENIZED PEPTIDES WHICH MAKES THE LIVER INJURY WORSE
the Hapten Hypothesis
46
SUSPECT DRUG IN THE HAPTEN HYPOTHESIS ARE:
``` halothane dihydralazine diclofenac phenytoin carbamazepine ```
47
THE SYMPTOMS OF DRUG INDUCED CHOLESTATIC INJURY ARE:
jaundice itch elevated levels of serum alkaline phosphatase
48
AN ENZYME WHICH REMOVES PHOSPHATE GROWTH AND AS A RESULT CAN DECREASE CELLULAR LEVELS OF ATP
ALKALINE PHOSPHATASE
49
THE DECREASED LEVELS OF ATP IN CHOLANGIOCYTES (EPITHELIAL CELLS OF THE BILE DUCT) CAN INDUCE PROFOUND INJURY RESULTING IN THE DEVELOPMENT OF ____ SYNDROME OR ____
DUCT VANISHING SYNDROME | DUCTOPENIA
50
bile salt export pump inhibited by some drugs are:
BSEP or ABCB11
51
In the majority of cases drug induced liver injury occurs unpredictably. This is called
idiosyncrotic action
52
These 3 factors determine the risk of the drug induced liver injury
host environment drug
53
examples of drug related risk factors are :
``` class dose duration drug-drug interaction ```
54
examples of host related risk factors are:
``` age sex weight metabolism genetic factors immune factors ```
55
examples of environment risk factors are:
diet cigarette smoke alcohol caffeine
56
these two drugs have been excluded from causing severe damage to elderly bc it induces injury mostly in younger patients and children
Valproate sodium | erythromycin
57
Being a female also induces liver injury with various drugs like ___
diclofenac
58
risk factors for this drug include chronic alcohol use and fasting
paracetamol (acetaminophen)
59
risk factors for this drug include obesity
halothane
60
risk factors for this drug include chronic alcohol use, obesity, diabetes mellitus, chronic hepatitis
methotrexate
61
A fraction of the acetaminophen is metabolized by ___, ____, and ____ to a toxic intermediate metabolite NAPQI that can interact with intracellular proteins and induce hepatocyte death
CYP2E1 CYP1A2 CYP3A4

Digestive System (8 decks)

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