Term
| Drugs that cause neurotoxicity have what main targets? |
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Definition
the neuron, the axon, the myelinating
cell or the neurotransmitter system |
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Term
Drugs attacking the neuron
(high metabolic rate, long cellular process supported my a cell body and has an excitable membrane that is constantly depolarizing/repolarizing) |
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Definition
CHLORAMPHENICOL,
DOXORUBICIN, ETHANOL, PHENYTOIN,
QUININE, STREPTOMYCIN
The initial assault is followed by apoptosis and permanent
loss of the neuron. Such a deficit often presents as a
diffuse encephalopathy, with global dysfunction. |
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Term
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Definition
| CHLOROQUINE, COLCHICINE, ISONIAZID, METRONIDAZOLE, NITROFURANTOIN, PACLITAXEL, CISPLATIN, VINCRISTINE) essentially produce a chemical “transection” of the nerve and the axon distal to this transection degenerates. In the PNS, partial to complete recovery can occur, whereas in the CNS, this damage is permanent. |
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Term
It is worthwhile here to highlight some of the anticancer
drugs (VINCA ALKALOIDS, TAXANES, PLATINUM
COMPOUNDS) and an anti-inflammatory drug
(COLCHICINE) use in the treatment of hyperuricemia
(gout). |
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Definition
He mechanism of action of these drugs involves
interruption in normal assembly/disassembly of
microtubules. Whereas these are important in the
mechanics of chromosomal separation and cell division,
they also play a vital role in transportation of cellular
materiel along the neuronal axon (see above). Blockade
of this process will, of necessity, lead to neuronal
damage concurrent with any anticancer drug effects. |
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Term
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Definition
AMIODARONE and DISULFIRAM.
Amiodarone is highly lipophilic and
forms intralysosomal lipid complexes, leading to inclusions in multiple tissues. These inclusions are seen
in neural structures, suggesting a possible mechanism of toxicity. Disulfiram attenuates glutamate uptake; the toxicity may arise from glutamate-induced neurotoxicity.
Note here that lead, an environmental toxin,produces
neurotoxicity by segmental demyelination. |
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Term
| NEUROTRANSMISSION INTERRUPTORS: |
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Definition
As the neurotransmitter systems are not localized in the
brain, and are often to also be found in peripheral
tissues/organs, the effects of interruption are not
localized
Most of the side effects of these drugs should be considered short-lived because they resolve upon
disappearance of the agonist/antagonist compounds.
Typical drug examples include NICOTINE, COCAINE and AMPHETAMINES. |
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Term
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Definition
Glutamate is the major
stimulatory neurotransmitter on the CNS. |
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Term
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Definition
Glutamate entry into the CNS is highly regulated by the
blood-brain barrier. Nevertheless, chemical that open
glutamate-dependent ion channels produce neuronal
swelling and neuronal death. Excessive glutamatergic
activity is considered to be neurotoxic. This signaling
system is implicated in the problem of neurodegeneration; |
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Term
| Typical drug-induced effects do what? |
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Definition
Involve the ions involved in the cardiac conduction cycle (Na+, Ca2+,
K+). This can be manifest in terms of alterations in the rate (chronotropic), force of contraction (inotropic) and
excitability (bathmotropic). It can also affect the heart
rhythm. In the vasculature, drugs can adversely affect
membrane structure and function. |
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Term
| GENERAL MECHANISMS OF CARDIOTOXICITY (1) |
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Definition
Drugs can inhibit cardiac Na+/K+-ATPase, which results
in increased resting intracellular Na+. This is exchanged
for Ca2+ via the Na+/Ca2+ exchange mechanism.
Increased intracellular Ca2+ and Ca2+ stores lead to
positive inotropic effects (see figure opposite). |
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Term
| GENERAL MECHANISMS OF CARDIOTOXICITY (2) |
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Definition
Agents that block Na+ channels lead to a reduction in conduction velocity, prolonged QRS duration (indicating
a change in the normal conduction cycle), and a “dampening down” in cardiac excitability. |
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Term
| GENERAL MECHANISMS OF CARDIOTOXICITY (3) |
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Definition
Agents that block K+ channels increase the period during which the cardiac cells are refractory to further
stimulation.
Agents blocking Ca2+ channels reduce the rate and
force of cardiac contractions via effects upon L-type and
T-type channels. |
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Term
Drugs can produce a vasoconstrictive effect upon heart vessels or thromboembolism lead to tissue ischemia.
The ischemia results in intracellular acidosis, inhibition of oxidative phosphorylation and depletion of ATP. Free radical damage, uncoupled oxidative phosphorylation and free radicals result in mitochondrial and sarcolemmal (principal Ca2+ storage organelle) damage. |
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Definition
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Term
| THERAPEUTIC FOCUS- ETHANOL (heart) |
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Definition
Metabolites of ETHANOL produce lipid peroxidation,oxidation of cytosolic components, sarcolemmal
dysfunction and damage to the contractile proteins actin
and myosin. |
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Term
| THERAPEUTIC FOCUS-CARDIAC GLYCOSIDES (heart) |
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Definition
| DIGOXIN, a drug used in the treatment of congestive heart failure works through inhibition of the Na+/K+- ATPase. In excess, this drug produces Ca2+ overload and arrhythmias. |
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Term
| THERAPEUTIC FOCUS-CARDIAC SYMPATHOMIMETICS (heart) |
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Definition
Drugs (ALLOPURINOL, ISOPROTERENOL,
ALBUTEROL, PSEUDOEPHEDRINE, AMPHETAMINE) producing a sympathomimetic effect (mimicking the
effects of epinephrine and norepinephrine) stimulate the
heart rate and increase O2 demand. If insufficiently supplied, mitochondrial and sarcolemmal damage ensue, lipid metabolism is altered and the net result becomes an apoptotic stimulus. |
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Term
| THERAPEUTIC FOCUS-ANTINEOPLASTICS (heart) |
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Definition
These drugs (DOXORUBICIN, FLUOROURACIL,
CYCLOPHOSPHAMIDE) may elicit a histamine release acutely, leading to tachycardia and cardiac arrhythmia.
Long-term exposure can produce tissue damage through other mechanisms that will not be covered here. |
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Term
| THERAPEUTIC FOCUS-CNS AGENTS (heart) |
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Definition
Some tricyclic antidepressants and antipsychotic agents
(AMITRYPTLLINE, FLUOXETINE, CLOZAPINE)
produce indirect effects upon the autonomic nervous system, which, in turn, impact cardiac activity. Some also produce a direct effect upon the ion channels in myocardial tissue leading to a negative inotropic action. |
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Term
| THERAPEUTIC FOCUS-GENERAL ANESTHETICS (heart) |
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Definition
Some agents (ISOFLURANE, SEVOFLURANE,
PROPOFOL) produce a sympathomimetic affect and block Ca2+ channels and impair Ca2+ homeostasis. |
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Term
| THERAPEUTIC FOCUS-ANTIMICROBIALS (heart) |
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Definition
| These drugs produce toxicity either by blocking Ca2+ mobilization (AMINOGLYCOSIDES, TETRACYCLINE, CHLORAMPHENICOL), or by K+ channel blockade (MACROLIDES, FLUOROQUINOLONES). |
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Term
| THERAPEUTIC FOCUS-ANTIFUGALS (heart) |
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Definition
AMPHOTERICIN interferes with cardiac membrane integrity, and produces Na+ and Ca2+ channel blockade.
FLUCYTOSINE is pro-arrhythmogenic and produces coronary artery vasospasm. |
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Term
| THERAPEUTIC FOCUS-ANTIVIRALS (heart) |
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Definition
Nucleoside reverse transcriptase inhibitors
(STAVUDINE, ZALCITABINE, ZIDOVUDINE) inhibit mitochondrial DNA polymerase, DNA and ATP synthesis. |
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Term
| THERAPEUTIC FOCUS-LOCAL ANESTHETICS (heart) |
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Definition
Local anesthetics (LIDOCAINE, BUPIVACAINE) block
voltage-gated Na+ channels and can affect both the heart and circulatory system if they become systematized in high concentration. |
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Term
| THERAPEUTIC FOCUS-hERG CHANNEL EFFECTS (heart) |
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Definition
Recall that the K+ channel is integral to normal cardiac conduction. As such, the ability of a drug to interact with these hERG channels is something that is examined as part of the drug development process. In recent years
the antihistamines astemizole and terfenadine were both removed from the market because they produced the classical arrhythmia known as Torsades. |
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Term
| Vascular endothelial cells (random info) |
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Definition
Vascular endothelial cells represent the “first line of defense” in preventing substances in the blood from
penetrating to deeper layers of the vessel wall. As such, they are particularly susceptible to injury. If the drug or toxin manages to reach the sub-endothelial space can
impact the viability of the underlying smooth muscle and
firbroblasts. |
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Term
| Common Mechanisms for Vascular Toxicity |
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Definition
These include alteration in
membrane structure and function, redox stress leading to disruption of gene regulatory mechanisms,
compromised antioxidant defenses (oxidized plasma lipoproteins are critical to the initiation and progression of atherosclerosis), generalized loss of homeostasis,
vessel-specific activation of pro-toxicants, and finally,
preferential accumulation of drug or toxin in vascular
tissues. |
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Term
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Definition
| CYCLOPHOSPHAMIDE – pulmonary epithelial lesions |
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Term
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Definition
High proliferative capacity
Carry O2
Circulation carries drugs/toxins
Thus, the consequences of
direct or indirect damage to blood components is predictable and potentially immediately life-threatening. |
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Term
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Definition
Reduced production or increased
destruction |
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Term
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Definition
Dependent upon a high rate
of cell division and a high rate of hemoglobin synthesis.
The latter is a common target for drug toxicity. Since iron deficiency, an essential component of heme, is usually a result of dietary deficiency or increased blood loss, drugs
producing blood loss can potentiate the risk of iron deficiency anemia. |
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Term
| Sideroblastic Anemia (and Drugs) |
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Definition
Defects in the porphyrin ring of heme.
Characteristics include an
accumulation of iron in bone
marrow erythroblasts. This
precipitates in the mitochondria causing injury
Chloramphenicol/ Isoniazid |
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Term
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Definition
Regarding the proliferative aspect of erythrocyte production, the continuous DNA synthetic effort is
demanding in terms of precursor molecules like thymidine. Deficiencies in either folate or vitamin B12,
essential for thymidine synthesis can give rise to megaloblastic anemia, a condition arising from improper cell division.
Vit B12- Antimetabolites
Folate- Omeprazole |
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Term
|
Definition
Aplastic anemia is a condition where the drug is toxic to the bone marrow progenitor cells and there is
consequently an insufficient replenishment of the blood
components. Aplastic anemia patients have lower counts of all three blood cell types: red blood cells, white blood cells, and platelets, termed pancytopenia.
ALLOPURINOL AND METHICILLIN |
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Term
FUNCTIONAL MODIFICATION OF HEMOGLOBIN
(methemoglobinemia) |
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Definition
Inherent in this structure is the capacity for iron in its customary ferrous state to become oxidized to ferric, thus forming methemoglobin. This moiety diminishes O2
carrying capacity and can significantly impair O2 tension in peripheral tissues. Normally the erythrocyte
metabolically converts the ferric back to the ferrous state, however a few local anesthetic drugs (e.g.,
BENZOCAINE, PRILOCAINE) can impair this process. |
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Term
| microangio-pathic anemia. |
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Definition
Normally the erythrocyte
has a lifespan in the circulation of ~120 days. Being anucleate, it has only limited protein synthetic capacity
and “ages” before ultimate “component (heme) recapture” by the spleen. Intravascular fragmentation of
erythrocytes can occur as a result of exposure to toxins, to infectious agents, and to some drugs, through the
process of oxidative hemolysis. This gives rise to schistocytes, fragmented cells in peripheral blood samples. |
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Term
| AMINOSALICYLIC ACID, PRIMAQUINE, and SULFASALAZINE do what? |
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Definition
The erythrocyte has inherent protective processes to guard against the continuous oxidative stress inherent in
this cell population. Such mechanisms include NADHdiaphorase,
superoxide dismutase, catalase, and the
glutathione pathway. A number of drugs and toxins carry the capacity, at high concentrations, to overwhelm these
protective mechanisms, leading to free radical mediated protein damage, destruction of hemoglobin, thioldependent enzyme and to the loss of structural integrity
of the erythrocyte membrane. |
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Term
| IMMUNE HEMOLYTIC ANEMIA and the drug that causes it |
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Definition
Immunologic destruction of erythrocytes is mediated by the interaction
of IgG or IgM antibodies with antigens expressed on the cell surface. With drug-induced hemolytic anemia it is
thought that the drug binds to the surface of the cell where it acts as a hapten, eliciting an immunologic
response. Antibodies only bind to hapten-coated cells. PENICILLIN is the drug most commonly associate with
this type of effect. |
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Term
| Quinidine and Methyldopa do what? |
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Definition
An alternative mechanism is for a drug, like QUINIDINE, to modify the erythrocyte membrane structure, again
eliciting an immune response. Finally, drugs like METHYLDOPA give rise to the production of an autoantibody that is indistinguishable from other
antibodies found during idiopathic autoimmune hemolytic anemia. |
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Term
Granulocytes
What do neutrophils do? |
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Definition
Leukocytes can be subdivided into neutrophils-eosinophils-basophils
(together known as granulocytes), monocytes and lymphocytes. Neutrophils, the largest component, are
highly specialized in the mediation of inflammation and
the ingestion and destruction of pathogenic microorganisms. |
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Term
| Importance of Granulocytes/Neutophils |
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Definition
blood cell component with a high proliferative rate, making it susceptible to anticancer drugs damaging DNA or impairing mitosis.
Setting aside these anticipated drug effects, there are, more importantly, idiosyncratic agranulocytic reactions to some drugs. These may give rise to a sudden depletion of circulating neutrophils following drug exposure
persisting until the drug is detoxified (metabolized) or eliminated. Where the drugs affect the non-committed
stem cell population, they may induce bone marrow failure. |
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Term
| Mechanisms for neutophil/granulocyte decrease and DRUGS! |
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Definition
Two mechanisms are recognized. The first involves a hapten-immune response phenomenon, the other is a direct toxic effect upon
granulopoiesis, possibly as a result of toxic oxidant accumulation following intracellular generation.
Associated with WBC Ab: AMPICILLIN
Not associated with WBC AB: ALLOPURINOL |
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Term
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Definition
1. first organ to encounter drugs
2. metabolic homeostasis
3. nutrient homeostasis, metabolism, formation of bile/secretion |
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Term
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Definition
Necrosis-the cell contents are liberated into the plasma where they can be detected by biochemical
assay (e.g., alanine aminotransferase [ALT] or γ-
glutamyltranspeptidase [GGT]). Where death by apoptosis (programmed cell death) transpires, this does
not lead to loss of cell contents. In terms of distribution, hepatocyte death can occur in a focal, zonal or
panacinar pattern. |
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Term
| Drugs causing Hepatic Cell Death |
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Definition
Mechanisms include lipid peroxidation, covalent binding to cellular macromolecules, mitochondrial damage,
disruption of the cell cytoskeleton, and massive Ca2+ influx. Common drugs producing hepatocyte death
include ACETAMINOPHEN and ETHANOL. |
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Term
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Definition
This is defined as a decrease in bile formation or impaired secretion of
certain components into bile. Increased serum levels of bile salts and bilirubin characterize it clinically. If the condition is severe or persistent enough, it produces
jaundice and produces bright yellow or dark brown urine. |
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Term
More about Cannilicular Cholestasis
(and Drugs) |
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Definition
Drugs producing cholestasis
do not necessarily act via one mechanism, and at only a single site.
Common drugs associated with cholestasis include CHLORPROMAZINE, CYCLOSPORIN A, and ESTROGENS. |
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Term
| Sinusoidal Damage (liver) |
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Definition
Occurs via dilation, by luminal occlusion (with red blood cells) or by damage to the endothelial lining. In consequence, the liver becomes
engorged with blood and the body goes into shock! Where endothelial tissue becomes damaged, this can
lead to rupture of integrity and again to entrapment of RBCs. Damage to the endothelium is considered an early indicator of the drug-induced
vascular disorder known as hepatic occlusive disease; this occurs in response to some herbal teas and
chemotherapeutics.
Common drugs associated with sinusoidal disorders include ANABOLIC STEROIDS and
CYCLOPHOSPHAMIDE. |
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Term
|
Definition
FATTY LIVER: This is hepatocyte
accumulation of lipid. ETHANOL is by far the most common agents producing this effect. |
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Term
Tylenol
(BIOACTIVATION AND DETOXIFICATION) |
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Definition
Liver metabolizes drugs. PhaseI reactions can "intoxify" and give rise to reactive species. Provided that
phase II substrates like glutathione and sulfate are available, these intermediates are only short lived and pose no significant problem. Where conjugate substrates are depleted, as in high doses of ACETAMINOPHEN, hepatic injury can occur. Recall TYLENOL OD is the #1 cause of acute hepatic failure in the US. Also note that chronic ETHANOL ingestion will induce CYPs and lead to alteration in metabolism of concurrent drugs. |
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Term
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Definition
Regarding ethanol itself, this agent is converted to acetaldehyde by alcohol dehydrogenase. Acetaldehyde
is subsequently converted into acetate by aldehyde dehydrogenase. Genetic variability in the activity of this
enzyme leads to the production of flushing and nausea due to acetaldehyde toxicity in those unfortunate enough
to possess the low capacity isoform! |
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Term
| IMMUNE REACTIONS in the liver (and drugs) |
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Definition
Hepatotoxicity leads to an influx
of inflammatory cells into the liver to assist in the removal of damaged cells. Compelling evidence for immune-mediated responses leading to hepatic damage only exist for ETHANOL and HALOTHANE. |
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Term
| MITOCHONDRIAL DAMAGE (liver) |
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Definition
Mitochondrial DNA codes for several proteins in the electron transport chain, and is at increase susceptibility to damage because it has
limited capacity for repair. ETHANOL in XS also leads to damage as a result of nicotinamide adenine dinucleotide
(NAD) depletion in connection with drug metabolism. Highly reactive aldehyde could accumulate in mitochondria, affecting the electron transport chain and potentially leading to generation of reactive O2 species. |
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Term
| IDIOSYNCRATIC INJURY (LIVER) That means we don’t know why they occur, albeit rarely. |
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Definition
Immune Mediated (ALLERGIC) reactions------- DICLOFENAC (analgesic)
Non-Immune-Mediated (ALLERGIC) reactions------- AMIODARONE (antiarrhythmic) |
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