Drug-induced liver injury Flashcards
Only a minority of drugs have a predictable dose-dependent injury called
direct hepatotoxic drug reactions
Most DILI occurs unpredictably called _____, and not dependently entirely on the dose of the drug
idiosyncratic drug reactions
Usually the drug metabolism in the liver involves the conversion of _____/_____ compound which is difficult to excrete
hydrophobic lipophilic
The reactions that are performed by the liver enzymes can be described as ___ and ____ biotransformation reaction
phase 1
phase 2
this reaction involves oxidation of cytochrome p450 enzyme
Phase
this reaction involves the conjugation of drug itself or metabolites from phase 1 to the polar ligands such as sulfate, glutathione or glucorinic acid
Phase2
Phase one oxidative reaction convert the mildly toxic drug into ___ ____ ___ bc these oxidation reactions make the chemicals very reactive
highly toxic intermediate METABOLITE
In some case the phase 2 products can be also ___ toxic
highly
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.
accumulate
Drugs causes liver injury by 4 pathological mechanisms
Hepatocellular or cytotoxic injury
Cholestasis
Neoplasms
Vascular injury
this pathophysiologic mechanism, the drug has a direct toxic affect on the liver cells and causes the hepatocytes necrosis/apoptosis.
Hepatocellular or cytotoxic injury
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
Cholestasis
some drugs that cause Hepatocellular or cytotoxic injury (direct affect on liver cells causing necrosis/apoptosis)
are
ACE inhibitors acetaminophen beta-blockers proton pump inhibitors statins amoxicillin
some drugs that cause that result in cholestasis (interfere with normal bile flow of liver) are
ACE inhibitors amoxicillin infliximab mesalamine sex steroids
drugs that cause vascular injury are
Contraceptive steroids, anabolic steroids
this pathophysiologic mechanism leads to hepatic vein thrombosis, peliosis hepatis
Vascular injury
some drugs that cause that lead to neoplasms
Anabolic steroids
sex steroids
Many drugs interfere with the ____ at the cellular membrane causing membrane blebbing, rupture, cell lyses
cytoskeleton
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
adduct
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
adduct
The central pro-inflammatory cytokines in TNFalpha and a pro-apoptic molecule is called
FAS ligand
Many drugs interfere with the ____ function which can cause accumulation of the ROS, innate damage, cellular death and the subsequent liver agents
mitochondrial
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
canaliculus
some mechanisms of DILI - drug induced liver injury are:
- inhibiting the transporters on the canaliculus membrane
- interfering with mitochondrial function
- binding to cellular proteins creating non-functional enzyme complex
previous, the max dose for acetaminophen was _____. today the suggested dose is ____
3900-4000mg
3000-3250mg
Exceeding the maximum recommended dose of acetaminophen, which is ___ g per day, can cause serious liver injury
4
> ___ of the cases of acute liver failure in the US are due to APAP (acetaminophen)
1/3
between 1998 to 2008, _____, which is ACETAMINOPHEN was THE LEADING CAUSE DILI
PARACETAMOL
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)
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
THIS CAUSES THE DEPLETION OF INTRACELLULAR GLUTATHIONE
NAPQI
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
NAPQI CAN CAUSE THE FOLLOWING EFFECTS:
Mitochondrial destruction loss of ATP Altered calcium homeostasis DNA damage intracellular protein modification
______ is a highly reactive two-electron moiety that can act as an electrophile or oxidant
NAPQI
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
____ IMMUNE SYSTEM IS AN IMPORTANT MODULATOR OF THE FINAL OUTCOME OF THE ACETOMENOPHEN INDUCED LIVER DAMAGE
INNATE
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
____ AND ___ FACTORS DETERMINE WHETHER THE PERSISTANT INFLAMMATION AND APOTOSIS WILL OCCUR OR IF IT WILL RESULT IN MILD INJURY AND HEPATOCYTES RECOVERY
INJURIOUS
PROTECTIVE
EXAMPLES OF PROTECTIVE CYTOKINES ARE:
INTERLEUKINS 6 & 10
INJURIOUS CYTOKINES ARE:
FASL
IFNy
TNF
THE ANTIDOTE FOR ACETAMINOPHEN INDUCED LIVER DAMAGE AND ACTEOMINOPHEN OVER DOSE IS
N-ACETYLCYSTEINE
FUNCTIONS OF N-ACETYLCYSTEINE
ARE:
-INCREASE GLUTATHIONE CONCENTRATION
ENHANCE SULFATE CONJUGATION
- ACTS AS ANTI-INFLAMMATORY/ANTIOXIDANT
- INCREASE NO CONC AND PROMOTE BLOOD FLOW
IF ADMINISTERED WITHIN 8 HOURS, IT WILL RESULT IN THE MAXIMUM HEPATO-PROTECTIVE EFFECT FOR ACUTE ACETAMINOPHEN INGESTION
N-ACETYLCYSTEINE
AN AGENT WHICH CAN INDUCE AN IMMUNE RESPONSE ONLY IF ITS BOUND TO CARRIER SUCH AS CELLULAR PROTEIN
HAPTEN
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
SUSPECT DRUG IN THE HAPTEN HYPOTHESIS ARE:
halothane dihydralazine diclofenac phenytoin carbamazepine
THE SYMPTOMS OF DRUG INDUCED CHOLESTATIC INJURY ARE:
jaundice
itch
elevated levels of serum alkaline phosphatase
AN ENZYME WHICH REMOVES PHOSPHATE GROWTH AND AS A RESULT CAN DECREASE CELLULAR LEVELS OF ATP
ALKALINE PHOSPHATASE
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
bile salt export pump inhibited by some drugs are:
BSEP or ABCB11
In the majority of cases drug induced liver injury occurs unpredictably. This is called
idiosyncrotic action
These 3 factors determine the risk of the drug induced liver injury
host
environment
drug
examples of drug related risk factors are :
class dose duration drug-drug interaction
examples of host related risk factors are:
age sex weight metabolism genetic factors immune factors
examples of environment risk factors are:
diet
cigarette smoke
alcohol
caffeine
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
Being a female also induces liver injury with various drugs like ___
diclofenac
risk factors for this drug include chronic alcohol use and fasting
paracetamol (acetaminophen)
risk factors for this drug include obesity
halothane
risk factors for this drug include chronic alcohol use, obesity, diabetes mellitus, chronic hepatitis
methotrexate
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
